Tropomyosin-related kinase (TRK) inhibitors

ABSTRACT

Tropomyosin-related kinase inhibitors (Trk inhibitors) are small molecule compounds useful in the treatment of disease. Trk inhibitors can be used as pharmaceutical agents and in pharmaceutical compositions. Trk inhibitors are useful in the treatment of inflammatory diseases, autoimmune disease, defects of bone metabolism and/or cancer, and are particularly useful in the treatment of osteoarthritis (OA), pain, and pain associated with OA. Trk inhibitors are also useful for inhibiting tropomyosin-related kinase A (TrkA), tropomyosin-related kinase B (TrkB), tropomyosin-related kinase C (TrkC), and/or c-FMS (the cellular receptor for colony stimulating factor-1 (CSF-1)).

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/194,696, filed Nov. 19, 2018, which is a continuation of U.S.application Ser. No. 15/436,195, now U.S. Pat. No. 10,166,239, filedFeb. 17, 2017, which is a continuation of U.S. application Ser. No.14/741,017, now U.S. Pat. No. 9,611,265, filed Jun. 16, 2015, which is acontinuation of U.S. application Ser. No. 14/628,876, now U.S. Pat. No.9,174,986, filed Feb. 23, 2015, which is a continuation of U.S.application Ser. No. 14/564,773, now U.S. Pat. No. 9,067,914, filed Dec.9, 2014, which claims the benefit of U.S. Provisional Application Nos.62/040,750, filed Aug. 22, 2014, and 61/914,128, filed Dec. 10, 2013.The above applications are incorporated by reference in entirety.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to tropomyosin-related kinase inhibitors (“Trkinhibitors”). This invention also relates to pharmaceutical compositionscomprising Trk inhibitors and to the use of Trk inhibitors andpharmaceutical compositions comprising Trk inhibitors to treat disease.This invention further relates to the use of Trk inhibitors to treatinflammatory diseases, autoimmune disease, defects of bone metabolismand cancer. The Trk inhibitors of the present invention can be used totreat osteoarthritis (OA), to treat pain, to treat post-operative pain,to treat pain associated with OA, and to inhibit tropomyosin-relatedkinase A (TrkA), tropomyosin-related kinase B (TrkB), and/ortropomyosin-related kinase C (TrkC), and to inhibit c-FMS (the cellularreceptor for colony stimulating factor-1 (CSF-1)).

Definitions

As used herein, the term “amino” means a functional group having anitrogen atom and 1 to 2 hydrogen atoms. “Amino” generally may be usedherein to describe a primary, secondary, or tertiary amine, and those ofskill in the art will readily be able to ascertain the identification ofwhich in view of the context in which this term is used in the presentdisclosure. The term “amine” or “amine group” or “ammonia group” means afunctional group containing a nitrogen atom derived from ammonia (NH₃).The amine groups are preferably primary amines, meaning the nitrogen isbonded to two hydrogen atoms and one substituent group comprising asubstituted or unsubstituted alkyl or aryl group or an aliphatic oraromatic group. The amine groups may be secondary amines meaning, thenitrogen is bonded to one hydrogen atom and two substituent groupscomprising a substituted or unsubstituted alkyl or aryl groups or analiphatic or aromatic group, as defined below. The amine groups may betertiary amines meaning the nitrogen is bonded to three substituentgroups comprising a substituted or unsubstituted alkyl or aryl groups oran aliphatic or aromatic group. The amine groups may also be quaternaryamines meaning the designated amine group is bonded to a fourth group,resulting in a positively charged ammonium group.

It is understood that any or all of the amines in the present inventionmay be in the free amine form (that is, as —NH₂ for a primary amine) orin a protonated form with a pharmaceutically acceptable anion (that is,as —NH₃ ⁺Y⁻ for a primary amine, where Y⁻ is the pharmaceuticallyacceptable anion).

As used herein, the term “amide group” means a functional groupcomprising a carbonyl group linked to a nitrogen. A “carbonyl group”means a functional group comprising a carbon atom double bonded to anoxygen atom, represented by (C═O).

The term “alkane” means a saturated hydrocarbon, bonded by single bonds.Alkanes can be linear or branched. “Cycloalkanes” are saturatedhydrocarbons rings bonded by single bonds.

As used herein, the term “(C₁-C₁₀)alkyl” means a saturated straightchained or branched or cyclic hydrocarbon consisting essentially of 1 to10 carbon atoms and a corresponding number of hydrogen atoms. Typicallystraight chained or branched groups have from one to ten carbons, ormore typically one to five carbons. Exemplary (C₁-C₁₀)alkyl groupsinclude methyl (represented by —CH₃), ethyl (represented by —CH₂—CH₃),n-propyl, isopropyl, n-butyl, isobutyl, etc. Other (C₁-C₁₀)alkyl groupswill be readily apparent to those of skill in the art given the benefitof the present disclosure.

As used herein, the term “(C₂-C₉)heteroalkyl” means a saturated straightchained or branched or cyclic hydrocarbon consisting essentially of 2 to10 atoms, wherein 2 to 9 of the atoms are carbon and the remainingatom(s) is selected from the group consisting of nitrogen, sulfur, andoxygen. Exemplary (C₂-C₉)heteroalkyl groups will be readily apparent tothose of skill in the art given the benefit of the present disclosure.

As used herein, the term “(C₃-C₁₀)cycloalkyl” means a nonaromaticsaturated hydrocarbon group, forming at least one ring consistingessential of 3 to 10 carbon atoms and a corresponding number of hydrogenatoms. (C₃-C₁₀)cycloalkyl groups can be monocyclic or multicyclic.Individual rings of multicyclic cycloalkyl groups can have differentconnectivities, for example, fused, bridged, spiro, etc., in addition tocovalent bond substitution. Exemplary (C₃-C₁₀)cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornanyl,bicyclo-octanyl, octahydro-pentalenyl, spiro-decanyl, cyclopropylsubstituted with cyclobutyl, cyclobutyl substituted with cyclopentyl,cyclohexyl substituted with cyclopropyl, etc. Other (C₃-C₁₀)cycloalkylgroups will be readily apparent to those of skill in the art given thebenefit of the present disclosure.

As used herein, the term “(C₂-C₉)heterocycloalkyl” means a nonaromaticgroup having 3 to 10 atoms that form at least one ring, wherein 2 to 9of the ring atoms are carbon and the remaining ring atom(s) is selectedfrom the group consisting of nitrogen, sulfur, and oxygen.(C₂-C₉)heterocycloalkyl groups can be monocyclic or multicyclic.Individual rings of such multicyclic heterocycloalkyl groups can havedifferent connectivities, for example, fused, bridged, spiro, etc., inaddition to covalent bond substitution. Exemplary(C₂-C₉)heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl,dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl,azetidinyl, oxiranyl, methylenedioxyl, chromenyl, barbituryl,isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,tetrahydroazepinyl, piperazinyl, piperizin-2-onyl, piperizin-3-onyl,chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, imidazolidinyl, 2-imidazolidinyl,1,4-dioxanyl, 8-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl,3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl,2,5-diazabicyclo[2.2.2]octanyl, octahydro-2H-pyrido[1,2-a]pyrazinyl,3-azabicyclo[4.1.0]heptanyl, 3-azabicyclo[3.1.0]hexanyl,2-azaspiro[4.4]nonanyl, 7-oxa-1-aza-spiro[4.4]nonanyl,7-azabicyclo[2.2.2]heptanyl, octahydro-1H-indolyl, etc. The(C₂-C₉)heterocycloalkyl group is typically attached to the mainstructure via a carbon atom or a nitrogen atom. Other(C₂-C₉)heterocycloalkyl groups will be readily apparent to those ofskill in the art given the benefit of the present disclosure.

The term “aliphatic group” or “aliphatic” means a non-aromatic groupconsisting of carbon and hydrogen, and may optionally include one ormore double and/or triple bonds. In other words, an aliphatic group isany group consisting of carbon and hydrogen which contains no aromaticfunctionality. An aliphatic group may be straight chained, branched orcyclic and typically contains between about one and about 24 carbonatoms.

The term “aryl group” may be used interchangeably with “aryl,” “arylring,” “aromatic,” “aromatic group,” and “aromatic ring.” Aryl groupsinclude carbocyclic aromatic groups, typically with six to fourteen ringcarbon atoms. Aryl groups also include heteroaryl groups, whichtypically have five to fourteen ring atoms with one or more heteroatomsselected from nitrogen, oxygen and sulfur.

As used herein, the term “(C₆-C₁₄)aryl” means an aromatic functionalgroup having 6 to 14 carbon atoms that form at least one ring.

As used herein, the term “(C₂-C₉)heteroaryl” means an aromaticfunctional group having 5 to 10 atoms that form at least one ring,wherein 2 to 9 of the ring atoms are carbon and the remaining ringatom(s) is selected from the group consisting of nitrogen, sulfur, andoxygen. (C₂-C₉)heteroaryl groups can be monocyclic or multicyclic.Individual rings of such multicyclic heteroaryl groups can havedifferent connectivities, for example, fused, etc., in addition tocovalent bond substitution. Exemplary (C₂-C₉)heteroaryl groups includefuryl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl,isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl,1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl,1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl,purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl,5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl and benzoxazinyl, etc. The (C₂-C₉)heteroarylgroup is typically attached to the main structure via a carbon atom,however, those of skill in the art will realize when certain otheratoms, for example, hetero ring atoms, can be attached to the mainstructure. Other (C₂-C₉)heteroaryl groups will be readily apparent tothose of skill in the art given the benefit of the present disclosure.

As used herein, the term “alkyl amine” means an (C₁-C₁₀)alkyl containinga primary, secondary, or tertiary amine group in place of one hydrogenatom, represented by (C₁-C₁₀)alkyl amine and ((C₁-C₁₀)alkyl)₂ amine.

The term “alkyl ester” means a (C₁-C₁₀)alkyl containing an ester groupin place of one hydrogen atom, represented by —O(O)C—(C₁-C₁₀)alkyl.

The term “alkyl acid” means an (C₁-C₁₀)alkyl containing a carboxylicacid group in place of one hydrogen atom, represented by(C₁-C₁₀)alkyl-COOH.

The term “aliphatic acid” means an acid of nonaromatic hydrocarbons,represented by (C₁-C₁₀)alkyl-COOH and (C₃-C₁₀)cycloalkyl-COOH.

The term “halo” means a fluorine (F), chlorine (Cl), bromine (Br),iodine (I), or astatine (At) ion.

The term “methoxy” means a (C₁)alkyl containing an oxygen in place ofone hydrogen atom, represented by —(O)CH₃.

The term “polyol” means an alcohol containing multiple hydroxyl (—OH)groups.

“Substituted” means the substitution of a carbon in alkyl, heterocyclicor aryl groups with one or more non-carbon substituents. Non-carbonsubstituents are selected from nitrogen, oxygen and sulfur.

“Unsubstituted” means the group is comprised of only hydrogen andcarbon.

A 3 to 10 member ring means a closed ring; the 3 to 10 member ring maybe acyclic, aromatic or heterocyclic.

The term “pharmaceutically acceptable anion” means an anion that issuitable for pharmaceutical use. Pharmaceutically acceptable anionsinclude but are not limited to halides, carbonate, bicarbonate, sulfate,bisulfate, hydroxide, nitrate, persulfate, phosphate, sulfite, acetate,ascorbate, benzoate, citrate, dihydrogen citrate, hydrogen citrate,oxalate, succinate, tartrate, taurocholate, glycocholate, and cholate.

The term “dicarbonyl” refers to an organic molecule containing two ormore adjacent carbonyl groups. Carbonyl groups, represented by C═O, canbe, for example, aldehydes, ketones, and other groups with an oxygenatom doubly bonded to a carbon atom. Examples include but are notlimited to glyoxal, methylglyoxal, dimethyl glyoxal, and3-deoxyglucosone.

Related Art

Not applicable

BRIEF SUMMARY OF THE INVENTION

The present invention relates to a compound with the structure ofFormula (I):

-   -   wherein:    -   n is 1, 2, 3, 4 or 5;    -   m is 0, 1, 2, 3 or 4;    -   Q¹ is H, halo or (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,        (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl,        -   wherein the (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,            (C₃-C₁₀)cycloalkyl, or (C₂-C₉)heterocycloalkyl is optionally            substituted by one to four groups selected from            (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,            (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,            (C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—,            COOH—(C₁-C₁₀)alkyl, COOH—(C₃-C₁₀)cycloalkyl,            (C₁-C₁₀)alkyl-O—, —OH, —NH₂, R⁷R⁸N—, R⁷R⁸N(O)C—, R⁷(O)CR⁸N—,            F₃C—, NC—, (C₃-C₁₀)alkyl(O)P—, (C₃-C₁₀)alkyl-S—,            (C₃-C₁₀)cycloalkyl-S—, (C₆-C₁₄)aryl-S—,            (C₂-C₉)heteroalkyl-S—, (C₂-C₉)heterocycloalkyl-S—,            (C₂-C₉)heteroaryl-S—, (C₃-C₁₀)alkyl(O)S—,            (C₃-C₁₀)cycloalkyl(O)S—, (C₆-C₁₄)aryl(O)S—,            (C₂-C₉)heteroalkyl(O)S—, (C₂-C₉)heterocycloalkyl(O)S—,            (C₂-C₉)heteroaryl(O)S—, (C₃-C₁₀)alkyl-O₂S—,            (C₃-C₁₀)cycloalkyl-O₂S—, (C₆-C₁₄)aryl-O₂S—,            (C₂-C₉)heteroalkyl-O₂S—, (C₂-C₉)heterocycloalkyl-O₂S—,            (C₂-C₉)heteroaryl-O₂S—, or R⁷R⁸NO₂S—,            -   wherein R⁷ and R⁸ is each independently H,                (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,                (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,                (C₂-C₉)heteroaryl;    -   Q² is (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl, (C₃-C₁₀)cycloalkyl, or        (C₂-C₉)heterocycloalkyl,        -   wherein the (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,            (C₃-C₁₀)cycloalkyl, or (C₂-C₉)heterocycloalkyl is optionally            substituted by one to four groups selected from            (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,            (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,            (C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—,            COOH—(C₁-C₁₀)alkyl, COOH—(C₃-C₁₀)cycloalkyl,            (C₁-C₁₀)alkyl-O—, —OH, —NH₂, R⁷R⁸N—, R⁷R⁸N(O)C—, R⁷(O)CR⁸N—,            F₃C—, NC—, (C₃-C₁₀)alkyl(O)P—, (C₃-C₁₀)alkyl-S—,            (C₃-C₁₀)cycloalkyl-S—, (C₆-C₁₄)aryl-S—,            (C₂-C₉)heteroalkyl-S—, (C₂-C₉)heterocycloalkyl-S—,            (C₂-C₉)heteroaryl-S—, (C₃-C₁₀)alkyl(O)S—,            (C₃-C₁₀)cycloalkyl(O)S—, (C₆-C₁₄)aryl(O)S—,            (C₂-C₉)heteroalkyl(O)S—, (C₂-C₉)heterocycloalkyl(O)S—,            (C₂-C₉)heteroaryl(O)S—, (C₃-C₁₀)alkyl-O₂S—,            (C₃-C₁₀)cycloalkyl-O₂S—, (C₆-C₁₄)aryl-O₂S—,            (C₂-C₉)heteroalkyl-O₂S—, (C₂-C₉)heterocycloalkyl-O₂S—,            (C₂-C₉)heteroaryl-O₂S—, or R⁷R⁸NO₂S—,            -   wherein R⁷ and R⁸ is each independently H,                (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,                (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,                (C₂-C₉)heteroaryl;    -   X is CH, N, halo or CR⁹,        -   wherein R⁹ is (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,            (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,            (C₂-C₉)heteroaryl, (C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—,            COOH—(C₁-C₁₀)alkyl, COOH—(C₃-C₁₀)cycloalkyl,            (C₁-C₁₀)alkyl-O—, —OH, —NH₂;    -   R¹ is H, halo, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,        (C₁-C₁₀)alkylamine, or NH₂;    -   R² is H, halo, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,        (C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-O—, or NH₂,    -   R³ and R⁴ are each independently H, (C₁-C₁₀)alkyl,        (C₂-C₉)heteroalkyl, (C₁-C₁₀)alkylamine, O—(C₁-C₁₀)alkyl, or NH₂        or R³ and R⁴ are taken together with the carbon to which they        are attached to form a 3 to 10 member ring,        -   wherein the 3 to 10 member ring is optionally substituted by            one to four groups selected from (C₁-C₁₀)alkyl,            (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,            (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,            (C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—,            COOH—(C₁-C₁₀)alkyl, COOH—(C₃-C₁₀)cycloalkyl,            (C₁-C₁₀)alkyl-O—, —OH, —NH₂; and    -   R⁵ and R⁶ are each independently H, (C₁-C₁₀)alkyl,        (C₂-C₉)heteroalkyl, (C₁-C₁₀)alkylamine, O—(C₁-C₁₀)alkyl, or NH₂        or R⁵ and R⁶ are taken together with the carbon to which they        are attached to form a 3 to 10 member ring,        -   wherein the 3 to 10 member ring is optionally substituted by            one to four groups selected from (C₁-C₁₀)alkyl,            (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,            (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,            (C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—,            COOH—(C₁-C₁₀)alkyl, COOH—(C₃-C₁₀)cycloalkyl,            (C₁-C₁₀)alkyl-O—, —OH, —NH₂;            or a pharmaceutically acceptable salt thereof.

The present invention further relates to a compound of Formula (I),wherein n is 1, 2, or 3.

The present invention further relates to a compound of Formula (I),wherein m is 0, 1, or 2.

The present invention further relates to a compound of Formula (I),wherein n is 1 and m is 1.

The present invention further relates to a compound of Formula (I),wherein Q¹ is H or (C₆-C₁₄)aryl or (C₂-C₉)heteroaryl wherein the(C₆-C₁₄)aryl or (C₂-C₉)heteroaryl is optionally substituted by one tofour groups selected from (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,(C₂-C₉)heteroaryl, (C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—,COOH—(C₁-C₁₀)alkyl, COOH—(C₃-C₁₀)cycloalkyl, (C₁-C₁₀)alkyl-O—, —OH,—NH₂, R⁷R⁸N—, R⁷R⁸N(O)C—, R⁷(O)CR⁸N—, F₃C—, NC—, (C₃-C₁₀)alkyl(O)P—,(C₃-C₁₀)alkyl-S—, (C₃-C₁₀)cycloalkyl-S—, (C₆-C₁₄)aryl-S—,(C₂-C₉)heteroalkyl-S—, (C₂-C₉)heterocycloalkyl-S—, (C₂-C₉)heteroaryl-S—,(C₃-C₁₀)alkyl(O)S—, (C₃-C₁₀)cycloalkyl(O)S—, (C₆-C₁₄)aryl(O)S—,(C₂-C₉)heteroalkyl(O)S—, (C₂-C₉)heterocycloalkyl(O)S—,(C₂-C₉)heteroaryl(O)S—, (C₃-C₁₀)alkyl-O₂S—, (C₃-C₁₀)cycloalkyl-O₂S—,(C₆-C₁₄)aryl-O₂S—, (C₂-C₉)heteroalkyl-O₂S—,(C₂-C₉)heterocycloalkyl-O₂S—, (C₂-C₉)heteroaryl-O₂S—, or R⁷R⁸NO₂S—,wherein R⁷ and R⁸ is each independently H, (C₁-C₁₀)alkyl,(C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl,(C₆-C₁₄)aryl, (C₂-C₉)heteroaryl.

The present invention further relates to a compound of Formula (I),wherein Q² is (C₆-C₁₄)aryl or (C₂-C₉)heteroaryl optionally substitutedby one to four groups selected from (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,(C₂-C₉)heteroaryl, (C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—,COOH—(C₁-C₁₀)alkyl, COOH—(C₃-C₁₀)cycloalkyl, (C₁-C₁₀)alkyl-O—, —OH,—NH₂, R⁷R⁸N—, R⁷R⁸N(O)C—, R⁷(O)CR⁸N—, F₃C—, NC—, (C₃-C₁₀)alkyl(O)P—,(C₃-C₁₀)alkyl-S—, (C₃-C₁₀)cycloalkyl-S—, (C₆-C₁₄)aryl-S—,(C₂-C₉)heteroalkyl-S—, (C₂-C₉)heterocycloalkyl-S—, (C₂-C₉)heteroaryl-S—,(C₃-C₁₀)alkyl(O)S—, (C₃-C₁₀)cycloalkyl(O)S—, (C₆-C₁₄)aryl(O)S—,(C₂-C₉)heteroalkyl(O)S—, (C₂-C₉)heterocycloalkyl(O)S—,(C₂-C₉)heteroaryl(O)S—, (C₃-C₁₀)alkyl-O₂S—, (C₃-C₁₀)cycloalkyl-O₂S—,(C₆-C₁₄)aryl-O₂S—, (C₂-C₉)heteroalkyl-O₂S—,(C₂-C₉)heterocycloalkyl-O₂S—, (C₂-C₉)heteroaryl-O₂S—, or R⁷R⁸NO₂S—,wherein R⁷ and R⁸ is each independently H, (C₁-C₁₀)alkyl,(C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl,(C₆-C₁₄)aryl, (C₂-C₉)heteroaryl.

The present invention further relates to a compound of Formula (I),wherein X is CH or N.

The present invention further relates to a compound of Formula (I),wherein R¹ is H, halo, NH₂, or (C₁-C₁₀)alkyl.

The present invention further relates to a compound of Formula (I),wherein R² is H, halo, (C₁-C₁₀)alkyl, or (C₁-C₁₀)alkyl-O—. The presentinvention further relates to a compound of Formula wherein R² is CH₃—O—,or CH₃—CH₂—O—.

The present invention further relates to a compound of Formula (I),wherein R³ and R⁴ are each H.

The present invention further relates to a compound of Formula (I),wherein R⁵ and R⁶ are each H.

The present invention further relates to a compound of Formula (I), withthe structure of Formula (II):

or a pharmaceutically acceptable salt thereof.

The present invention further relates to pharmaceutical compositionscomprising a compound of Formula (I).

The present invention further relates to methods of treatinginflammatory diseases, autoimmune disease, defects of bone metabolism orcancer in a patient in need thereof comprising administering to thepatient a compound according to Formula (I).

The present invention further relates to methods of treatingosteoarthritis in a patient in need thereof comprising administering tothe patient a compound according to Formula (I).

The present invention further relates to methods of treating pain in apatient in need thereof comprising administering to the patient acompound according to Formula (I).

The present invention further relates to methods of treating painassociated with osteoarthritis in a patient in need thereof comprisingadministering to the patient a compound according to Formula (I).

The present invention further relates to methods of inhibitingtropomyosin-related kinase A in a patient comprising administering tothe patient a compound according to Formula (I).

The present invention further relates to methods of inhibitingtropomyosin-related kinase B in a patient comprising administering tothe patient a compound according to Formula (I).

The present invention further relates to methods of inhibitingtropomyosin-related kinase C in a patient comprising administering tothe patient a compound according to Formula (I).

The present invention further relates to methods of inhibiting c-FMS ina patient comprising administering to the patient a compound accordingto Formula (I).

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

Not applicable

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to tropomyosin-related kinase inhibitors (Trkinhibitors). This invention also relates to pharmaceutical compositionscomprising Trk inhibitors and to the use of Trk inhibitors andpharmaceutical compositions comprising Trk inhibitors to treat disease.This invention further relates to the use of Trk inhibitors to treatinflammatory diseases, autoimmune disease, defects of bone metabolismand cancer. The Trk inhibitors of the present invention can be used totreat osteoarthritis (OA), to treat pain associated with OA, and toinhibit tropomyosin-related kinase A (TrkA), tropomyosin-related kinaseB (TrkB), tropomyosin-related kinase C (TrkC), and to inhibit c-FMS (thecellular receptor for colony stimulating factor-1 (CSF-1)).

Tropomyosin-related kinases (Trk) are high affinity receptors activatedby soluble growth factors called neutrophins (NT). TrkA, also known asneurotrophic tyrosine kinase receptor type 1, is activated by nervegrowth factor (NGF). TrkB is activated by brain derived growth factorand NT-4/5. TrkC is activated by NT3. The activation of Trk leads to theactivation of downstream kinases that are implicated in cell signaling,including cell proliferation, survival, angiogenesis and metastasis. Trkhave been implicated in a number of diseases, including OA.

The invention also relates to inhibitors of c-FMS (the cellular receptorfor colony stimulating factor-1 (CSF-1). C-FMS plays a role in theregulation of macrophage function, and is believed to play a role ininflammatory diseases, autoimmune disease, defects of bone metabolismand cancer (Burns and Wilks, 2011, Informa Healthcare).

OA is a prevalent and debilitating joint disease characterized bychronic pain and destruction of articular cartilage. Recent clinicaltrials have confirmed a role for blocking NGF in OA knee pain,demonstrating significant pain relief and high responder rates inpatients treated by intravenous infusion with anti-NGF blockingantibodies (Lane, 2010, N Engl J Med). However, this modality may leadto an increased risk for adverse events due to systemic inhibition ofNGF signaling (FDA Arthritis Advisory Committee Meeting to DiscussSafety Issues Related to the Anti-Nerve Growth Factor Agents)Accordingly, a novel approach toward targeting NGF-mediated OA pain hasbeen adopted through the development of Trk inhibitors, specificallyTrkA inhibitors, the high-affinity receptor for NGF (Nicol, 2007,Molecular Interv). The Trk inhibitors of the present invention aredelivered locally and thereby avoid the systemic distribution observedwith intravenous anti-NGF administration. This treatment strategyprovides enhanced dosing convenience, as well greater safety by allowingfor the maintenance of physiologically necessary NGF signaling (i.e.sensory/sympathetic nerve maintenance, angiogenesis) at non-local sites.

The Trk inhibitors of the present invention are benzimidazolederivatives. The Trk inhibitors are small molecules for localadministration.

This invention relates to pharmaceutical compositions comprising Trkinhibitors. This invention also relates to methods of inhibiting Trkwith Trk inhibitors and methods of treating disease with Trk inhibitors.The invention also pertains to methods of treating OA, methods withtreating pain, and methods of treating post-operative pain, and methodsof treating pain associated with OA with Trk inhibitors. The Trkinhibitors and the pharmaceutical compositions comprising Trk inhibitorscan be administered in multiple dosage forms, including an injection forlocal delivery. The Trk inhibitors are the active pharmaceuticalingredient in pharmaceutical compositions comprising Trk inhibitors; theTrk inhibitors can also be co-administered and/or co-formulated withother active ingredients for the treatment of disease, including OA andpain associated with OA.

The present invention relates to a compound with the structure ofFormula (I):

-   -   wherein:    -   n is 1, 2, 3, 4 or 5;    -   m is 0, 1, 2, 3 or 4;    -   Q¹ is H, halo or (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,        (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl,        -   wherein the (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,            (C₃-C₁₀)cycloalkyl, or (C₂-C₉)heterocycloalkyl is optionally            substituted by one to four groups selected from            (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,            (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,            (C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—,            COOH—(C₁-C₁₀)alkyl, COOH—(C₃-C₁₀)cycloalkyl,            (C₁-C₁₀)alkyl-O—, —OH, —NH₂, R⁷R⁸N—, R⁷R⁸N(O)C—, R⁷(O)CR⁸N—,            F₃C—, NC—, (C₃-C₁₀)alkyl(O)P—, (C₃-C₁₀)alkyl-S—,            (C₃-C₁₀)cycloalkyl-S—, (C₆-C₁₄)aryl-S—,            (C₂-C₉)heteroalkyl-S—, (C₂-C₉)heterocycloalkyl-S—,            (C₂-C₉)heteroaryl-S—, (C₃-C₁₀)alkyl(O)S—,            (C₃-C₁₀)cycloalkyl(O)S—, (C₆-C₁₄)aryl(O)S—,            (C₂-C₉)heteroalkyl(O)S—, (C₂-C₉)heterocycloalkyl(O)S—,            (C₂-C₉)heteroaryl(O)S—, (C₃-C₁₀)alkyl-O₂S—,            (C₃-C₁₀)cycloalkyl-O₂S—, (C₆-C₁₄)aryl-O₂S—,            (C₂-C₉)heteroalkyl-O₂S—, (C₂-C₉)heterocycloalkyl-O₂S—,            (C₂-C₉)heteroaryl-O₂S—, or R⁷R⁸NO₂S—,            -   wherein R⁷ and R⁸ is each independently H,                (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,                (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,                (C₂-C₉)heteroaryl;    -   Q² is (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl, (C₃-C₁₀)cycloalkyl, or        (C₂-C₉)heterocycloalkyl,        -   wherein the (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,            (C₃-C₁₀)cycloalkyl, or (C₂-C₉)heterocycloalkyl is optionally            substituted by one to four groups selected from            (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,            (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,            (C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—,            COOH—(C₁-C₁₀)alkyl, COOH—(C₃-C₁₀)cycloalkyl,            (C₁-C₁₀)alkyl-O—, —OH, —NH₂, R⁷R⁸N—, R⁷R⁸N(O)C—, R⁷(O)CR⁸N—,            F₃C—, NC—, (C₃-C₁₀)alkyl(O)P—, (C₃-C₁₀)alkyl-S—,            (C₃-C₁₀)cycloalkyl-S—, (C₆-C₁₄)aryl-S—,            (C₂-C₉)heteroalkyl-S—, (C₂-C₉)heterocycloalkyl-S—,            (C₂-C₉)heteroaryl-S—, (C₃-C₁₀)alkyl(O)S—,            (C₃-C₁₀)cycloalkyl(O)S—, (C₆-C₁₄)aryl(O)S—,            (C₂-C₉)heteroalkyl(O)S—, (C₂-C₉)heterocycloalkyl(O)S—,            (C₂-C₉)heteroaryl(O)S—, (C₃-C₁₀)alkyl-O₂S—,            (C₃-C₁₀)cycloalkyl-O₂S—, (C₆-C₁₄)aryl-O₂S—,            (C₂-C₉)heteroalkyl-O₂S—, (C₂-C₉)heterocycloalkyl-O₂S—,            (C₂-C₉)heteroaryl-O₂S—, or R⁷R⁸NO₂S—,            -   wherein R⁷ and R⁸ is each independently H,                (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,                (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,                (C₂-C₉)heteroaryl;    -   X is CH, N, halo or CR⁹,        -   wherein R⁹ is (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,            (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,            (C₂-C₉)heteroaryl, (C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—,            COOH—(C₁-C₁₀)alkyl, COOH—(C₃-C₁₀)cycloalkyl,            (C₁-C₁₀)alkyl-O—, —OH, —NH₂;    -   R¹ is H, halo, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,        (C₁-C₁₀)alkylamine, or NH₂;    -   R² is H, halo, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,        (C₁-C₁₀)alkylamine, (C₁-C₁)alkyl-O—, or NH₂;    -   R³ and R⁴ are each independently H, (C₁-C₁₀)alkyl,        (C₂-C₉)heteroalkyl, (C₁-C₁₀)alkylamine, O—(C₁-C₁₀)alkyl, or NH₂        or R³ and R⁴ are taken together with the carbon to which they        are attached to form a 3 to 10 member ring,        -   wherein the 3 to 10 member ring is optionally substituted by            one to four groups selected from (C₁-C₁₀)alkyl,            (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,            (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,            (C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—,            COOH—(C₁-C₁₀)alkyl, COOH—(C₃-C₁₀)cycloalkyl,            (C₁-C₁₀)alkyl-O—, —OH, —NH₂; and    -   R⁵ and R⁶ are each independently H, (C₁-C₁₀)alkyl,        (C₂-C₉)heteroalkyl, (C₁-C₁)alkylamine, O—(C₁-C₁₀)alkyl, or NH₂        or R⁵ and R⁶ are taken together with the carbon to which they        are attached to form a 3 to 10 member ring,        -   wherein the 3 to 10 member ring is optionally substituted by            one to four groups selected from (C₁-C₁₀)alkyl,            (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,            (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,            (C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—,            COOH—(C₁-C₁₀)alkyl, COOH—(C₃-C₁₀)cycloalkyl,            (C₁-C₁₀)alkyl-O—, —OH, —NH₂;            or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the present invention relates to a compoundof Formula (I), wherein n is 1, 2, or 3. In another embodiment, thepresent invention relates to a compound of Formula (I), wherein n is 1.In another embodiment, the present invention relates to a compound ofFormula (I), wherein n is 2. In yet another embodiment, the presentinvention relates to a compound of Formula (I), wherein n is 3.

In a preferred embodiment, the present invention relates to a compoundof Formula (I), wherein m is 0, 1, or 2. In another embodiment, thepresent invention relates to a compound of Formula (I), wherein m is 0.In another embodiment, the present invention relates to a compound ofFormula (I), wherein m is 1. In yet another embodiment, the presentinvention relates to a compound of Formula (I), wherein m is 2.

In a preferred embodiment, the present invention relates to a compoundof Formula (I), wherein n is 1 and m is 1.

In a preferred embodiment, the present invention further relates to acompound of Formula (I), wherein Q¹ is H or (C₆-C₁₄)aryl or(C₂-C₉)heteroaryl optionally substituted by one to four groups selectedfrom (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,(C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,(C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—, COOH—(C₁-C₁₀)alkyl,COOH—(C₃-C₁₀)cycloalkyl, (C₁-C₁₀)alkyl-O—, —OH, —NH₂, R⁷R⁸N—,R⁷R⁸N(O)C—, R⁷(O)CR⁸N—, F₃C—, NC—, (C₃-C₁₀)alkyl(O)P—, (C₃-C₁₀)alkyl-S—,(C₃-C₁₀)cycloalkyl-S—, (C₆-C₁₄)aryl-S—, (C₂-C₉)heteroalkyl-S—,(C₂-C₉)heterocycloalkyl-S—, (C₂-C₉)heteroaryl-S—, (C₃-C₁₀)alkyl(O)S—,(C₃-C₁₀)cycloalkyl(O)S—, (C₆-C₁₄)aryl(O)S—, (C₂-C₉)heteroalkyl(O)S—,(C₂-C₉)heterocycloalkyl(O)S—, (C₂-C₉)heteroaryl(O)S—,(C₃-C₁₀)alkyl-O₂S—, (C₃-C₁₀)cycloalkyl-O₂S—, (C₆-C₁₄)aryl-O₂S—,(C₂-C₉)heteroalkyl-O₂S—, (C₂-C₉)heterocycloalkyl-O₂S—,(C₂-C₉)heteroaryl-O₂S—, or R⁷R⁸NO₂S—, wherein R⁷ and R⁸ is eachindependently H, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,(C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl. In anotherembodiment, the present invention further relates to a compound ofFormula (I), wherein Q¹ is H. In yet another embodiment, the presentinvention further relates to a compound of Formula (I), wherein Q¹ is(C₆-C₁₄)aryl optionally substituted by one to four groups selected from(C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,(C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,(C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—, COOH—(C₁-C₁₀)alkyl,COOH—(C₃-C₁₀)cycloalkyl, (C₁-C₁₀)alkyl-O—, —OH, —NH₂, R⁷R⁸N—,R⁷R⁸N(O)C—, R⁷(O)CR⁸N—, F₃C—, NC—, (C₃-C₁₀)alkyl(O)P—, (C₃-C₁₀)alkyl-S—,(C₃-C₁₀)cycloalkyl-S—, (C₆-C₁₄)aryl-S—, (C₂-C₉)heteroalkyl-S—,(C₂-C₉)heterocycloalkyl-S—, (C₂-C₉)heteroaryl-S—, (C₃-C₁₀)alkyl(O)S—,(C₃-C₁₀)cycloalkyl(O)S—, (C₆-C₁₄)aryl(O)S—, (C₂-C₉)heteroalkyl(O)S—,(C₂-C₉)heterocycloalkyl(O)S—, (C₂-C₉)heteroaryl(O)S—,(C₃-C₁₀)alkyl-O₂S—, (C₃-C₁₀)cycloalkyl-O₂S—, (C₆-C₁₄)aryl-O₂S—,(C₂-C₉)heteroalkyl-O₂S—, (C₂-C₉)heterocycloalkyl-O₂S—,(C₂-C₉)heteroaryl-O₂S—, or R⁷R⁸NO₂S—, wherein R⁷ and R⁸ is eachindependently H, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,(C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl. In yet anotherembodiment, the present invention further relates to a compound ofFormula (I), wherein Q¹ is (C₂-C₉)heteroaryl optionally substituted byone to four groups selected from (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,(C₂-C₉)heteroaryl, (C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—,COOH—(C₁-C₁₀)alkyl, COOH—(C₃-C₁₀)cycloalkyl, (C₁-C₁₀)alkyl-O—, —OH,—NH₂, R⁷R⁸N—, R⁷R⁸N(O)C—, R⁷(O)CR⁸N—, F₃C—, NC—, (C₃-C₁₀)alkyl(O)P—,(C₃-C₁₀)alkyl-S—, (C₃-C₁₀)cycloalkyl-S—, (C₆-C₁₄)aryl-S—,(C₂-C₉)heteroalkyl-S—, (C₂-C₉)heterocycloalkyl-S—, (C₂-C₉)heteroaryl-S—,(C₃-C₁₀)alkyl(O)S—, (C₃-C₁₀)cycloalkyl(O)S—, (C₆-C₁₄)aryl(O)S—,(C₂-C₉)heteroalkyl(O)S—, (C₂-C₉)heterocycloalkyl(O)S—,(C₂-C₉)heteroaryl(O)S—, (C₃-C₁₀)alkyl-O₂S—, (C₃-C₁₀)cycloalkyl-O₂S—,(C₆-C₁₄)aryl-O₂S—, (C₂-C₉)heteroalkyl-O₂S—,(C₂-C₉)heterocycloalkyl-O₂S—, (C₂-C₉)heteroaryl-O₂S—, or R⁷R⁸NO₂S—,wherein R⁷ and R⁸ is each independently H, (C₁-C₁₀)alkyl,(C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl,(C₆-C₁₄)aryl, (C₂-C₉)heteroaryl.

In a preferred embodiment, the present invention further relates to acompound of Formula (I), wherein Q² is (C₆-C₁₄)aryl or (C₂-C₉)heteroaryloptionally substituted by one to four groups selected from(C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,(C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,(C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—, COOH—(C₁-C₁₀)alkyl,COOH—(C₃-C₁₀)cycloalkyl, (C₁-C₁₀)alkyl-O—, —OH, —NH₂, R⁷R⁸N—,R⁷R⁸N(O)C—, R⁷(O)CR⁸N—, F₃C—, NC—, (C₃-C₁₀)alkyl(O)P—, (C₃-C₁₀)alkyl-S—,(C₃-C₁₀)cycloalkyl-S—, (C₆-C₁₄)aryl-S—, (C₂-C₉)heteroalkyl-S—,(C₂-C₉)heterocycloalkyl-S—, (C₂-C₉)heteroaryl-S—, (C₃-C₁₀)alkyl(O)S—,(C₃-C₁₀)cycloalkyl(O)S—, (C₆-C₁₄)aryl(O)S—, (C₂-C₉)heteroalkyl(O)S—,(C₂-C₉)heterocycloalkyl(O)S—, (C₂-C₉)heteroaryl(O)S—,(C₃-C₁₀)alkyl-O₂S—, (C₃-C₁₀)cycloalkyl-O₂S—, (C₆-C₁₄)aryl-O₂S—,(C₂-C₉)heteroalkyl-O₂S—, (C₂-C₉)heterocycloalkyl-O₂S—,(C₂-C₉)heteroaryl-O₂S—, or R⁷R⁸NO₂S—, wherein R⁷ and R⁸ is eachindependently H, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,(C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl. In anotherembodiment, the present invention further relates to a compound ofFormula (I), wherein Q² is (C₆-C₁₄)aryl optionally substituted by one tofour groups selected from (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,(C₂-C₉)heteroaryl, (C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—,COOH—(C₁-C₁₀)alkyl, COOH—(C₃-C₁₀)cycloalkyl, (C₁-C₁₀)alkyl-O—, —OH,—NH₂, R⁷R⁸N—, R⁷R⁸N(O)C—, R⁷(O)CR⁸N—, F₃C—, NC—, (C₃-C₁₀)alkyl(O)P—,(C₃-C₁₀)alkyl-S—, (C₃-C₁₀)cycloalkyl-S—, (C₆-C₁₄)aryl-S—,(C₂-C₉)heteroalkyl-S—, (C₂-C₉)heterocycloalkyl-S—, (C₂-C₉)heteroaryl-S—,(C₃-C₁₀)alkyl(O)S—, (C₃-C₁₀)cycloalkyl(O)S—, (C₆-C₁₄)aryl(O)S—,(C₂-C₉)heteroalkyl(O)S—, (C₂-C₉)heterocycloalkyl(O)S—,(C₂-C₉)heteroaryl(O)S—, (C₃-C₁₀)alkyl-O₂S—, (C₃-C₁₀)cycloalkyl-O₂S—,(C₆-C₁₄)aryl-O₂S—, (C₂-C₉)heteroalkyl-O₂S—,(C₂-C₉)heterocycloalkyl-O₂S—, (C₂-C₉)heteroaryl-O₂S—, or R⁷R⁸NO₂S—,wherein R⁷ and R⁸ is each independently H, (C₁-C₁₀)alkyl,(C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl,(C₆-C₁₄)aryl, (C₂-C₉)heteroaryl. In yet another embodiment, the presentinvention further relates to a compound of Formula (I), wherein Q² is(C₂-C₉)heteroaryl optionally substituted by one to four groups selectedfrom (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,(C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,(C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—, COOH—(C₁-C₁₀)alkyl,COOH—(C₃-C₁₀)cycloalkyl, (C₁-C₁₀)alkyl-O—, —OH, —NH₂, R⁷R⁸N—,R⁷R⁸N(O)C—, R⁷(O)CR⁸N—, F₃C—, NC—, (C₃-C₁₀)alkyl(O)P—, (C₃-C₁₀)alkyl-S—,(C₃-C₁₀)cycloalkyl-S—, (C₆-C₁₄)aryl-S—, (C₂-C₉)heteroalkyl-S—,(C₂-C₉)heterocycloalkyl-S—, (C₂-C₉)heteroaryl-S—, (C₃-C₁₀)alkyl(O)S—,(C₃-C₁₀)cycloalkyl(O)S—, (C₆-C₁₄)aryl(O)S—, (C₂-C₉)heteroalkyl(O)S—,(C₂-C₉)heterocycloalkyl(O)S—, (C₂-C₉)heteroaryl(O)S—,(C₃-C₁₀)alkyl-O₂S—, (C₃-C₁₀)cycloalkyl-O₂S—, (C₆-C₁₄)aryl-O₂S—,(C₂-C₉)heteroalkyl-O₂S—, (C₂-C₉)heterocycloalkyl-O₂S—,(C₂-C₉)heteroaryl-O₂S—, or R⁷R⁸NO₂S—, wherein R⁷ and R⁸ is eachindependently H, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,(C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl.

In a preferred embodiment, the present invention further relates to acompound of Formula (I), wherein X is CH or N. In another embodiment,the present invention further relates to a compound of Formula (I),wherein X is CH. In yet another embodiment the present invention furtherrelates to a compound of Formula (I), wherein X is N.

In a preferred embodiment, the present invention further relates to acompound of Formula (I), wherein R¹ is H, halo, NH₂, or (C₁-C₁₀)alkyl.In another embodiment, the present invention further relates to acompound of Formula (I), wherein R¹ is H. In another embodiment, thepresent invention further relates to a compound of Formula (I), whereinR¹ is halo. In another embodiment, the present invention further relatesto a compound of Formula (I), wherein R¹ is NH₂. In yet anotherembodiment, the present invention further relates to a compound ofFormula (I), wherein R¹ is (C₁-C₁₀)alkyl.

In a preferred embodiment, the present invention relates to a compoundof Formula (I), wherein R² is H, halo, (C₁-C₁₀)alkyl, or(C₁-C₁₀)alkyl-O—. In another embodiment, the present invention relatesto a compound of Formula (I), wherein R² is H. In another embodiment,the present invention relates to a compound of Formula (I), wherein R²is halo. In another embodiment, the present invention relates to acompound of Formula (I), wherein R² is (C₁-C₁₀)alkyl. In anotherembodiment, the present invention relates to a compound of Formula (I),wherein R² is (C₁-C₁₀)alkyl-O—. In yet another embodiment, the presentinvention relates to a compound of Formula (I), wherein R² is CH₃—O—, orCH₃—CH₂—O—.

In a preferred embodiment, the present invention relates to a compoundof Formula (I), wherein R³ and R⁴ are each H.

In a preferred embodiment, the present invention relates to a compoundof Formula (I), wherein R⁵ and R⁶ are each H.

In a preferred embodiment, present invention relates to a compound ofFormula (I), with the structure of Formula (II):

or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the present invention relates to a compoundof Formula (II), wherein n is 1, 2, or 3. In another embodiment, thepresent invention relates to a compound of Formula (II), wherein n is 1.In another embodiment, the present invention relates to a compound ofFormula (II), wherein n is 2. In yet another embodiment, the presentinvention relates to a compound of Formula (II), wherein n is 3.

In a preferred embodiment, the present invention relates to a compoundof Formula (II), wherein m is 0, 1, or 2. In another embodiment, thepresent invention relates to a compound of Formula (II), wherein m is 0.In another embodiment, the present invention relates to a compound ofFormula (II), wherein m is 1. In yet another embodiment, the presentinvention relates to a compound of Formula (II), wherein m is 2.

In a preferred embodiment, the present invention relates to a compoundof Formula (II), wherein n is 1 and m is 1.

In a preferred embodiment, the present invention further relates to acompound of Formula (II), wherein Q¹ is H or (C₆-C₁₄)aryl or(C₂-C₉)heteroaryl optionally substituted by one to four groups selectedfrom (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,(C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,(C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—, COOH—(C₁-C₁₀)alkyl,COOH—(C₃-C₁₀)cycloalkyl, (C₁-C₁₀)alkyl-O—, —OH, —NH₂, R⁷R⁸N—,R⁷R⁸N(O)C—, R⁷(O)CR⁸N—, F₃C—, NC—, (C₃-C₁₀)alkyl(O)P—, (C₃-C₁₀)alkyl-S—,(C₃-C₁₀)cycloalkyl-S—, (C₆-C₁₄)aryl-S—, (C₂-C₉)heteroalkyl-S—,(C₂-C₉)heterocycloalkyl-S—, (C₂-C₉)heteroaryl-S—, (C₃-C₁₀)alkyl(O)S—,(C₃-C₁₀)cycloalkyl(O)S—, (C₆-C₁₄)aryl(O)S—, (C₂-C₉)heteroalkyl(O)S—,(C₂-C₉)heterocycloalkyl(O)S—, (C₂-C₉)heteroaryl(O)S—,(C₃-C₁₀)alkyl-O₂S—, (C₃-C₁₀)cycloalkyl-O₂S—, (C₆-C₁₄)aryl-O₂S—,(C₂-C₉)heteroalkyl-O₂S—, (C₂-C₉)heterocycloalkyl-O₂S—,(C₂-C₉)heteroaryl-O₂S—, or R⁷R⁸NO₂S—, wherein R⁷ and R⁸ is eachindependently H, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,(C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl. In anotherembodiment, the present invention further relates to a compound ofFormula (II), wherein Q¹ is H. In yet another embodiment, the presentinvention further relates to a compound of Formula (II), wherein Q¹ is(C₆-C₁₄)aryl optionally substituted by one to four groups selected from(C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,(C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,(C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—, COOH—(C₁-C₁₀)alkyl,COOH—(C₃-C₁₀)cycloalkyl, (C₁-C₁₀)alkyl-O—, —OH, —NH₂, R⁷R⁸N—,R⁷R⁸N(O)C—, R⁷(O)CR⁸N—, F₃C—, NC—, (C₃-C₁₀)alkyl(O)P—, (C₃-C₁₀)alkyl-S—,(C₃-C₁₀)cycloalkyl-S—, (C₆-C₁₄)aryl-S—, (C₂-C₉)heteroalkyl-S—,(C₂-C₉)heterocycloalkyl-S—, (C₂-C₉)heteroaryl-S—, (C₃-C₁₀)alkyl(O)S—,(C₃-C₁₀)cycloalkyl(O)S—, (C₆-C₁₄)aryl(O)S—, (C₂-C₉)heteroalkyl(O)S—,(C₂-C₉)heterocycloalkyl(O)S—, (C₂-C₉)heteroaryl(O)S—,(C₃-C₁₀)alkyl-O₂S—, (C₃-C₁₀)cycloalkyl-O₂S—, (C₆-C₁₄)aryl-O₂S—,(C₂-C₉)heteroalkyl-O₂S—, (C₂-C₉)heterocycloalkyl-O₂S—,(C₂-C₉)heteroaryl-O₂S—, or R⁷R⁸NO₂S—, wherein R⁷ and R⁸ is eachindependently H, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,(C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl. In yet anotherembodiment, the present invention further relates to a compound ofFormula (II), wherein Q¹ is (C₂-C₉)heteroaryl optionally substituted byone to four groups selected from (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,(C₂-C₉)heteroaryl, (C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—,COOH—(C₁-C₁₀)alkyl, COOH—(C₃-C₁₀)cycloalkyl, (C₁-C₁₀)alkyl-O—, —OH,—NH₂, R⁷R⁸N—, R⁷R⁸N(O)C—, R⁷(O)CR⁸N—, F₃C—, NC—, (C₃-C₁₀)alkyl(O)P—,(C₃-C₁₀)alkyl-S—, (C₃-C₁₀)cycloalkyl-S—, (C₆-C₁₄)aryl-S—,(C₂-C₉)heteroalkyl-S—, (C₂-C₉)heterocycloalkyl-S—, (C₂-C₉)heteroaryl-S—,(C₃-C₁₀)alkyl(O)S—, (C₃-C₁₀)cycloalkyl(O)S—, (C₆-C₁₄)aryl(O)S—,(C₂-C₉)heteroalkyl(O)S—, (C₂-C₉)heterocycloalkyl(O)S—,(C₂-C₉)heteroaryl(O)S—, (C₃-C₁₀)alkyl-O₂S—, (C₃-C₁₀)cycloalkyl-O₂S—,(C₆-C₁₄)aryl-O₂S—, (C₂-C₉)heteroalkyl-O₂S—,(C₂-C₉)heterocycloalkyl-O₂S—, (C₂-C₉)heteroaryl-O₂S—, or R⁷R⁸NO₂S—,wherein R⁷ and R⁸ is each independently H, (C₁-C₁₀)alkyl,(C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl,(C₆-C₁₄)aryl, (C₂-C₉)heteroaryl.

In a preferred embodiment, the present invention further relates to acompound of Formula (II), wherein Q² is (C₆-C₁₄)aryl or(C₂-C₉)heteroaryl optionally substituted by one to four groups selectedfrom (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,(C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,(C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—, COOH—(C₁-C₁₀)alkyl,COOH—(C₃-C₁₀)cycloalkyl, (C₁-C₁₀)alkyl-O—, —OH, —NH₂, R⁷R⁸N—,R⁷R⁸N(O)C—, R⁷(O)CR⁸N—, F₃C—, NC—, (C₃-C₁₀)alkyl(O)P—, (C₃-C₁₀)alkyl-S—,(C₃-C₁₀)cycloalkyl-S—, (C₆-C₁₄)aryl-S—, (C₂-C₉)heteroalkyl-S—,(C₂-C₉)heterocycloalkyl-S—, (C₂-C₉)heteroaryl-S—, (C₃-C₁₀)alkyl(O)S—,(C₃-C₁₀)cycloalkyl(O)S—, (C₆-C₁₄)aryl(O)S—, (C₂-C₉)heteroalkyl(O)S—,(C₂-C₉)heterocycloalkyl(O)S—, (C₂-C₉)heteroaryl(O)S—,(C₃-C₁₀)alkyl-O₂S—, (C₃-C₁₀)cycloalkyl-O₂S—, (C₆-C₁₄)aryl-O₂S—,(C₂-C₉)heteroalkyl-O₂S—, (C₂-C₉)heterocycloalkyl-O₂S—,(C₂-C₉)heteroaryl-O₂S—, or R⁷R⁸NO₂S—, wherein R⁷ and R⁸ is eachindependently H, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,(C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl. In anotherembodiment, the present invention further relates to a compound ofFormula (II), wherein Q² is (C₆-C₁₄)aryl optionally substituted by oneto four groups selected from (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl,(C₂-C₉)heteroaryl, (C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—,COOH—(C₁-C₁₀)alkyl, COOH—(C₃-C₁₀)cycloalkyl, (C₁-C₁₀)alkyl-O—, —OH,—NH₂, R⁷R⁸N—, R⁷R⁸N(O)C—, R⁷(O)CR⁸N—, F₃C—, NC—, (C₃-C₁₀)alkyl(O)P—,(C₃-C₁₀)alkyl-S—, (C₃-C₁₀)cycloalkyl-S—, (C₆-C₁₄)aryl-S—,(C₂-C₉)heteroalkyl-S—, (C₂-C₉)heterocycloalkyl-S—, (C₂-C₉)heteroaryl-S—,(C₃-C₁₀)alkyl(O)S—, (C₃-C₁₀)cycloalkyl(O)S—, (C₆-C₁₄)aryl(O)S—,(C₂-C₉)heteroalkyl(O)S—, (C₂-C₉)heterocycloalkyl(O)S—,(C₂-C₉)heteroaryl(O)S—, (C₃-C₁₀)alkyl-O₂S—, (C₃-C₁₀)cycloalkyl-O₂S—,(C₆-C₁₄)aryl-O₂S—, (C₂-C₉)heteroalkyl-O₂S—,(C₂-C₉)heterocycloalkyl-O₂S—, (C₂-C₉)heteroaryl-O₂S—, or R⁷R⁸NO₂S—,wherein R⁷ and R⁸ is each independently H, (C₁-C₁₀)alkyl,(C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl,(C₆-C₁₄)aryl, (C₂-C₉)heteroaryl. In yet another embodiment, the presentinvention further relates to a compound of Formula (II), wherein Q² is(C₂-C₉)heteroaryl optionally substituted by one to four groups selectedfrom (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,(C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,(C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—, COOH—(C₁-C₁₀)alkyl,COOH—(C₃-C₁₀)cycloalkyl, (C₁-C₁₀)alkyl-O—, —OH, —NH₂, R⁷R⁸N—,R⁷R⁸N(O)C—, R⁷(O)CR⁸N—, F₃C—, NC—, (C₃-C₁₀)alkyl(O)P—, (C₃-C₁₀)alkyl-S—,(C₃-C₁₀)cycloalkyl-S—, (C₆-C₁₄)aryl-S—, (C₂-C₉)heteroalkyl-S—,(C₂-C₉)heterocycloalkyl-S—, (C₂-C₉)heteroaryl-S—, (C₃-C₁₀)alkyl(O)S—,(C₃-C₁₀)cycloalkyl(O)S—, (C₆-C₁₄)aryl(O)S—, (C₂-C₉)heteroalkyl(O)S—,(C₂-C₉)heterocycloalkyl(O)S—, (C₂-C₉)heteroaryl(O)S—,(C₃-C₁₀)alkyl-O₂S—, (C₃-C₁₀)cycloalkyl-O₂S—, (C₆-C₁₄)aryl-O₂S—,(C₂-C₉)heteroalkyl-O₂S—, (C₂-C₉)heterocycloalkyl-O₂S—,(C₂-C₉)heteroaryl-O₂S—, or R⁷R⁸NO₂S—, wherein R⁷ and R⁸ is eachindependently H, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,(C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl.

In a preferred embodiment, the present invention further relates to acompound of Formula (II), wherein X is CH or N. In another embodiment,the present invention further relates to a compound of Formula (II),wherein X is CH. In yet another embodiment the present invention furtherrelates to a compound of Formula (II), wherein X is N.

In a preferred embodiment, the present invention further relates to acompound of Formula (II), wherein R¹ is H, halo, NH₂, or (C₁-C₁₀)alkyl.In another embodiment, the present invention further relates to acompound of Formula (II), wherein R¹ is H. In another embodiment, thepresent invention further relates to a compound of Formula (II), whereinR¹ is halo. In another embodiment, the present invention further relatesto a compound of Formula (II), wherein R¹ is NH₂. In yet anotherembodiment, the present invention further relates to a compound ofFormula (II), wherein R¹ is (C₁-C₁₀)alkyl.

In a preferred embodiment, the present invention relates to a compoundof Formula (II), wherein R² is H, halo, (C₁-C₁₀)alkyl, or(C₁-C₁₀)alkyl-O—. In another embodiment, the present invention relatesto a compound of Formula (II), wherein R² is H. In another embodiment,the present invention relates to a compound of Formula (II), wherein R²is halo. In another embodiment, the present invention relates to acompound of Formula (II), wherein R² is (C₁-C₁₀)alkyl. In anotherembodiment, the present invention relates to a compound of Formula (II),wherein R² is (C₁-C₁₀)alkyl-O—. In yet another embodiment, the presentinvention relates to a compound of Formula (II), wherein R² is CH₃—O—,or CH₃—CH₂—O—.

In a preferred embodiment, the present invention further relates to acompound of Formula (I), wherein the compound is selected from:

-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyrimidin-5-yl)-1H-benzo[d]imidazol-2-amine,-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyridine-4-yl)-1H-benzo[d]imidazol-2-amine,-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine,-   (5-(2-Amino-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-5-yl)pyridin-2-yl)dimethylphosphine    oxide,-   3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine,-   1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-benzo[d]imidazole,-   3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine,-   (5-(2-Amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)dimethylphosphine    oxide,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine,-   2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)piperidin-4-yl)propan-2-amine,-   4-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)morpholine,-   6-(4-Cyclopropylpiperazin-1-yl)-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(2,7-diazaspiro[3.5]nonan-2-yl)-3H-imidazo[4,5-b]pyridine-   (S)-1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyrrolidine-2-carboxylic    acid,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine-   3-(3-Methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine,-   3-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazole,-   2-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,3,4-oxadiazole,-   2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-1,2,3-triazol-4-yl)propan-2-amine,    and-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-3H-imidazo[4,5-b]pyridine.

In a preferred embodiment, the present invention further relates to apharmaceutical composition comprising a compound according to Formula(I). In yet another preferred embodiment, the present invention furtherrelates to a pharmaceutical composition comprising a compound accordingto Formula (II). In another embodiment, the present invention furtherrelates to a pharmaceutical composition comprising a compound accordingto Formula (I) wherein the compound is selected from:

-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyrimidin-5-yl)-1H-benzo[d]imidazol-2-amine,-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyridine-4-yl)-1H-benzo[d]imidazol-2-amine,-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine,-   (5-(2-Amino-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-5-yl)pyridin-2-yl)dimethylphosphine    oxide,-   3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine,-   1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-benzo[d]imidazole,-   3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine,-   (5-(2-Amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)dimethylphosphine    oxide,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine,-   2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)piperidin-4-yl)propan-2-amine,-   4-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)morpholine,-   6-(4-Cyclopropylpiperazin-1-yl)-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(2,7-diazaspiro[3.5]nonan-2-yl)-3H-imidazo[4,5-b]pyridine-   (S)-1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyrrolidine-2-carboxylic    acid,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine-   3-(3-Methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine,-   3-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazole,-   2-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,3,4-oxadiazole,-   2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-1,2,3-triazol-4-yl)propan-2-amine,    and-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-3H-imidazo[4,5-b]pyridine.

In a preferred embodiment, the present invention further relates tomethods of treating inflammatory diseases, autoimmune disease, defectsof bone metabolism or cancer comprising administering to the patient acompound according to Formula (I). In yet another preferred embodiment,the present invention further relates to methods of treatinginflammatory diseases, autoimmune disease, defects of bone metabolism orcancer comprising administering to the patient a compound according toFormula (II). In another embodiment, the present invention furtherrelates to methods of treating inflammatory diseases, autoimmunedisease, defects of bone metabolism or cancer comprising administeringto the patient a compound according to Formula (I) wherein the compoundis selected from:

-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyrimidin-5-yl)-1H-benzo[d]imidazol-2-amine,-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyridine-4-yl)-1H-benzo[d]imidazol-2-amine,-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine,-   (5-(2-Amino-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-5-yl)pyridin-2-yl)dimethylphosphine    oxide,-   3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine,-   1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-benzo[d]imidazole,-   3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine,-   (5-(2-Amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)dimethylphosphine    oxide,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine,-   2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)piperidin-4-yl)propan-2-amine,-   4-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)morpholine,-   6-(4-Cyclopropylpiperazin-1-yl)-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(2,7-diazaspiro[3.5]nonan-2-yl)-3H-imidazo[4,5-b]pyridine-   (S)-1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyrrolidine-2-carboxylic    acid,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine-   3-(3-Methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine,-   3-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazole,-   2-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,3,4-oxadiazole,-   2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-1,2,3-triazol-4-yl)propan-2-amine,    and-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-3H-imidazo[4,5-b]pyridine.

In a preferred embodiment, the present invention further relates tomethods of treating osteoarthritis comprising administering to thepatient a compound according to Formula (I). In yet another preferredembodiment, the present invention further relates to methods of treatingosteoarthritis comprising administering to the patient a compoundaccording to Formula (II). In another embodiment, the present inventionfurther relates to methods of treating osteoarthritis comprisingadministering to the patient a compound according to Formula (I) whereinthe compound is selected from:

-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyrimidin-5-yl)-1H-benzo[d]imidazol-2-amine,-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyridine-4-yl)-1H-benzo[d]imidazol-2-amine,-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine,-   (5-(2-Amino-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-5-yl)pyridin-2-yl)dimethylphosphine    oxide,-   3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine,-   1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-benzo[d]imidazole,-   3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine,-   (5-(2-Amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)dimethylphosphine    oxide,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine,-   2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)piperidin-4-yl)propan-2-amine,-   4-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)morpholine,-   6-(4-Cyclopropylpiperazin-1-yl)-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(2,7-diazaspiro[3.5]nonan-2-yl)-3H-imidazo[4,5-b]pyridine-   (S)-1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyrrolidine-2-carboxylic    acid,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine-   3-(3-Methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine,-   3-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazole,-   2-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,3,4-oxadiazole,-   2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-1,2,3-triazol-4-yl)propan-2-amine,    and-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-3H-imidazo[4,5-b]pyridine.

In a preferred embodiment, the present invention further relates tomethods of treating pain comprising administering to the patient acompound according to Formula (I). In an embodiment, the pain treated bythe compound according to Formula (I) is post-operative pain. In yetanother preferred embodiment, the present invention further relates tomethods of treating pain comprising administering to the patient acompound according to Formula (II). In another embodiment, the paintreated by the compound according to Formula (II) is post-operativepain. In another embodiment, the present invention further relates tomethods of treating pain and methods of treating post-operative paincomprising administering to the patient a compound according to Formula(I) wherein the compound is selected from:

-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine,-   3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine,-   (5-(2-Amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)dimethylphosphine    oxide,-   3-(3-Methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine,    and-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine.

In a preferred embodiment, the present invention further relates tomethods of treating pain associated with osteoarthritis comprisingadministering to the patient a compound according to Formula (I). In yetanother preferred embodiment, the present invention further relates tomethods of treating pain associated with osteoarthritis comprisingadministering to the patient a compound according to Formula (II). Inanother embodiment, the present invention further relates to methods oftreating pain associated with osteoarthritis comprising administering tothe patient a compound according to Formula (I) wherein the compound isselected from:

-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyrimidin-5-yl)-1H-benzo[d]imidazol-2-amine,-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyridine-4-yl)-1H-benzo[d]imidazol-2-amine,-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine,-   (5-(2-Amino-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-5-yl)pyridin-2-yl)dimethylphosphine    oxide,-   3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine,-   1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-benzo[d]imidazole,-   3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine,-   (5-(2-Amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)dimethylphosphine    oxide,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine,-   2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)piperidin-4-yl)propan-2-amine,-   4-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)morpholine,-   6-(4-Cyclopropylpiperazin-1-yl)-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(2,7-diazaspiro[3.5]nonan-2-yl)-3H-imidazo[4,5-b]pyridine-   (S)-1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyrrolidine-2-carboxylic    acid,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine-   3-(3-Methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine,-   3-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazole,-   2-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,3,4-oxadiazole,-   2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-1,2,3-triazol-4-yl)propan-2-amine,    and-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-3H-imidazo[4,5-b]pyridine.

In a preferred embodiment, the present invention further relates tomethods of inhibiting tropomyosin-related kinase A comprisingadministering to the patient a compound according to Formula (I). In yetanother preferred embodiment, the present invention further relates tomethods of inhibiting tropomyosin-related kinase A comprisingadministering to the patient a compound according to Formula (II). Inanother embodiment, the present invention further relates to methods ofinhibiting tropomyosin-related kinase A comprising administering to thepatient a compound according to Formula (I) wherein the compound isselected from:

-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyrimidin-5-yl)-1H-benzo[d]imidazol-2-amine,-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyridine-4-yl)-1H-benzo[d]imidazol-2-amine,-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine,-   (5-(2-Amino-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-5-yl)pyridin-2-yl)dimethylphosphine    oxide,-   3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine,-   1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-benzo[d]imidazole,-   3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine,-   (5-(2-Amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)dimethylphosphine    oxide,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine,-   2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)piperidin-4-yl)propan-2-amine,-   4-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)morpholine,-   6-(4-Cyclopropylpiperazin-1-yl)-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(2,7-diazaspiro[3.5]nonan-2-yl)-3H-imidazo[4,5-b]pyridine-   (S)-1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyrrolidine-2-carboxylic    acid,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine-   3-(3-Methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine,-   3-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazole,-   2-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,3,4-oxadiazole,-   2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-1,2,3-triazol-4-yl)propan-2-amine,    and-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-3H-imidazo[4,5-b]pyridine.

In a preferred embodiment, the present invention further relates tomethods of inhibiting tropomyosin-related kinase B comprisingadministering to the patient a compound according to Formula (I). In yetanother preferred embodiment, the present invention further relates tomethods of inhibiting tropomyosin-related kinase B comprisingadministering to the patient a compound according to Formula (II). Inanother embodiment, the present invention further relates to methods ofinhibiting tropomyosin-related kinase B comprising administering to thepatient a compound according to Formula (I) wherein the compound isselected from:

-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyrimidin-5-yl)-1H-benzo[d]imidazol-2-amine,-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyridine-4-yl)-1H-benzo[d]imidazol-2-amine,-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine,-   (5-(2-Amino-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-5-yl)pyridin-2-yl)dimethylphosphine    oxide,-   3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine,-   1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-benzo[d]imidazole,-   3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine,-   (5-(2-Amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)dimethylphosphine    oxide,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine,-   2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)piperidin-4-yl)propan-2-amine,-   4-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)morpholine,-   6-(4-Cyclopropylpiperazin-1-yl)-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(2,7-diazaspiro[3.5]nonan-2-yl)-3H-imidazo[4,5-b]pyridine-   (S)-1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyrrolidine-2-carboxylic    acid,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine-   3-(3-Methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine,-   3-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazole,-   2-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,3,4-oxadiazole,-   2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-1,2,3-triazol-4-yl)propan-2-amine,    and-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-3H-imidazo[4,5-b]pyridine.

In a preferred embodiment, the present invention further relates tomethods of inhibiting tropomyosin-related kinase C comprisingadministering to the patient a compound according to Formula (I). In yetanother preferred embodiment, the present invention further relates tomethods of inhibiting tropomyosin-related kinase C comprisingadministering to the patient a compound according to Formula (II). Inanother embodiment, the present invention further relates to methods ofinhibiting tropomyosin-related kinase C comprising administering to thepatient a compound according to Formula (I) wherein the compound isselected from:

-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyrimidin-5-yl)-1H-benzo[d]imidazol-2-amine,-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyridine-4-yl)-1H-benzo[d]imidazol-2-amine,-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine,-   (5-(2-Amino-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-5-yl)pyridin-2-yl)dimethylphosphine    oxide,-   3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine,-   1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-benzo[d]imidazole,-   3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine,-   (5-(2-Amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)dimethylphosphine    oxide,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine,-   2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)piperidin-4-yl)propan-2-amine,-   4-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)morpholine,-   6-(4-Cyclopropylpiperazin-1-yl)-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(2,7-diazaspiro[3.5]nonan-2-yl)-3H-imidazo[4,5-b]pyridine-   (S)-1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyrrolidine-2-carboxylic    acid,-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine-   3-(3-Methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine,-   3-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazole,-   2-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,3,4-oxadiazole,-   2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-1,2,3-triazol-4-yl)propan-2-amine,    and-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-3H-imidazo[4,5-b]pyridine.

In a preferred embodiment, the present invention further relates tomethods of inhibiting c-FMS comprising administering to the patient acompound according to Formula (I). In yet another preferred embodiment,the present invention further relates to methods of inhibiting c-FMScomprising administering to the patient a compound according to Formula(II). In another embodiment, the present invention further relates tomethods of inhibiting c-FMS comprising administering to the patient acompound according to Formula (I) wherein the compound is selected from:

-   1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine,-   3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine,-   (5-(2-Amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)dimethylphosphine    oxide,-   3-(3-Methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine,    and-   3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine.

Non-limiting examples of suitable Trk inhibitors according to Formula(I) are presented in Table 1. It is understood that any the structurespresented in Table 1 also include pharmaceutically acceptable saltsthereof. Preferred pharmaceutically acceptable anions include but arenot limited to halides, carbonate, bicarbonate, sulfate, bisulfate,hydroxide, nitrate, persulfate, phosphate, sulfite, acetate, ascorbate,benzoate, citrate, dihydrogen citrate, hydrogen citrate, oxalate,succinate, tartrate, taurocholate, glycocholate, and cholate. Mostpreferred pharmaceutically acceptable anions include chloride,carbonate, and bicarbonate.

TABLE 1 Trk Inhibitors Example No. Compound Name Compound Structure Ex.3-1 1-(3-Methoxy-4-((4- methoxybenzyl)oxy)benzyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H- benzo[d]imidazol-2-amine

Ex. 3-2-1 1-(3-Methoxy-4-((4- methoxybenzyl)oxy)benzyl)-5-(pyrimidin-5-yl)-1H- benzo[d]imidazol-2-amine

Ex. 3-2-2 1-(3-Methoxy-4-((4- methoxybenzyl)oxy)benzyl)-5-(pyridine-4-yl)-1H- benzo[d]imidazol-2-amine

Ex. 3-2-3 1-(3-Methoxy-4-((4- methoxybenzyl)oxy)benzyl)-5-(1-(2-morpholinoethyl)-1H-pyrazol- 4-yl)-1H-benzo[d]imidazol-2- amine

Ex. 3-3 (5-(2-Amino-1-(3-methoxy-4-((4- methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-5-yl)pyridin-2- yl)dimethylphosphine oxide

Ex. 3-4 1-(3-Methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-5-(pyrimidin- 5-yl)-1H-benzo[d]imidazole

Ex. 3-5 3-(3-methoxy-4-((6- methoxypyridin-3- yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)- 3H-imidazo[4,5-b]pyridine

Ex. 3-6 1-(3-Methoxy-4-((6- methoxypyridin-3- yl)methoxy)benzyl)-5-(4-(piperidin-3-yl)-1H-1,2,3-triazol- 1-yl)-1H-benzo[d]imidazole

Ex. 3-7 2-(1-(3-Methoxy-4-((6- methoxypyridin-3- yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-5- (piperidin-4-yl)-1,3,4-oxadiazole

Ex. 3-8 1-(3-Methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-5-(piperidin- 4-yl)-1H-benzo[d]imidazole

Ex. 3-9 4-(1-(3-Methoxy-4-((6- methoxypyridin-3- yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)morpholine

Ex. 3-10 2-(1-(1-(3-Methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-1H- benzo[d]imidazol-5-yl)piperidin-4-yl)propan-2-amine

Ex. 3-11 1-(3-methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-5-(2,7- diazaspiro[3.5]nonan-2-yl)-1H-benzo[d]imidazole

Ex. 3-12 1-(1-(3-Methoxy-4-((6- methoxypyridin-3- yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)piperidin- 4-amine

Ex. 3-13 1-(3-Methoxy-4-((6- methoxypyridin-3- yl)methoxy)benzyl)-5-(4-methylpiperazin-1-yl)-1H- benzo[d]imidazole

Ex. 3-14 1-(2-Amino-1-(3-methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-1H- benzo[d]imidazol-5-yl)-4- methylpiperazin-2-one

Ex. 3-15 3-(3-Methoxy-4-((4- methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H- imidazo[4,5-b]pyridin-2-amine

Ex. 3-16 (5-(2-Amino-3-(3-methoxy-4-((4- methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-6- yl)pyridin-2-yl)dimethylphosphine oxide

Ex. 3-17 3-(3-Methoxy-4-((6- methoxypyridin-3- yl)methoxy)benzyl)-6-(4-methylpiperazin-1-yl)-3H- imidazo[4,5-b]pyridine

Ex. 3-18-1 2-(1-(3-(3-Methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-3H- imidazo[4,5-b]pyridin-6-yl)piperidin-4-yl)propan-2- amine

Ex. 3-18-2 4-(3-(3-Methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-3H- imidazo[4,5-b]pyridin-6- yl)morpholine

Ex. 3-18-3 6-(4-Cyclopropylpiperazin-1-yl)- 3-(3-methoxy-4-((6-methoxypyridin-3- yl)methoxy)benzyl)-3H- imidazo[4,5-b]pyridine

Ex. 3-18-4 4-(3-(3-Methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-3H- imidazo[4,5-b]pyridin-6-yl)-1,4-diazabicyclo[3.2.2]nonane

Ex. 3-18-5 3-(3-Methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-6-(2,7- diazaspiro[3.5]nonan-2-yl)-3H-imidazo[4,5-b]pyridine

Ex. 3-18-6 1-(3-(3-Methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-3H- imidazo[4,5-b]pyridin-6- yl)piperidin-4-amine

Ex. 3-18-7 (S)-1-(3-(3-Methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-3H- imidazo[4,5-b]pyridin-6-yl)pyrrolidine-2-carboxylic acid

Ex. 3-19 3-(3-Methoxy-4-((6- methoxypyridin-3- yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)- 3H-imidazo[4,5-b]pyridine

Ex. 3-20 3-(3-Methoxy-4-((6- methylpyridin-3- yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)- 3H-imidazo[4,5-b]pyridine

Ex. 3-21 3-(3-(3-Methoxy-4-((6- methoxypyridin-3- yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5- (piperidin-4-yl)-1,2,4-oxadiazole

Ex. 3-22 3-(1-(3-Methoxy-4-((6- methoxypyridin-3- yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-5- (piperidin-4-yl)-1,2,4-oxadiazole

Ex. 3-23 2-(3-(3-Methoxy-4-((6- methoxypyridin-3- yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5- (piperidin-4-yl)-1,3,4-oxadiazole

Ex. 3-24 2-(1-(3-(3-Methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-3H- imidazo[4,5-b]pyridin-6-yl)-1H-1,2,3-triazol-4-yl)propan-2-amine

Ex. 3-25 3-(3-Methoxy-4-((6- methoxypyridin-3- yl)methoxy)benzyl)-6-(4-(piperidin-3-yl)-1H-1,2,3-triazol- 1-yl)-3H-imidazo[4,5-b]pyridine

Ex. 3-26 1-(3-methoxy-4-((6- methoxypyridin-3- yl)methoxy)benzyl)-5-(4-methylpiperazin-1-yl)-1H- benzo[d]imidazol-2-amine

Ex. 3-27 1-(2-fluoro-5-methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-5-(4- methylpiperazin-1-yl)-1H- benzo[d]imidazole

Ex. 3-28 3-(3-Ethoxy-4-((6- methoxypyridin-3- yl)methoxy)benzyl)-6-(4-methylpiperazin-1-yl)-3H- imidazo[4,5-b]pyridine

Ex. 3-29 1-(1-(3-Methoxy-4-((6- methoxypyridin-3- yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-4- methylpiperazin-2-one

Ex. 3-30 3-(3-Methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-6-(5-methyl- 1-azabicyclo[3.2.1]oct-6-en-7-yl)-3H-imidazo[4,5-b]pyridine

Ex. 3-31 1-(3-methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-5-(5-methyl- 1-azabicyclo[3.2.1]oct-6-en-7-yl)-1H-benzo[d]imidazole

Ex. 3-32 7-(3-(3-methoxy-4-((6- methoxypyridin-3- yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1- azabicyclo[3.2.1]oct-6-en-5-ol

Ex. 3-33 7-(1-(3-Methoxy-4-((6- methoxypyridin-3- yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-1- azabicyclo[3.2.1]oct-6-en-5-ol

Ex. 3-34 3-(3-methoxy-4-(1-(6- methoxypyridin-3-yl)propoxy)benzyl)-6-(1- methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

Ex. 3-35-1 3-(3-methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-6-(1- methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

Ex. 3-35-2 3-(3-methoxy-4-((6- (trifluoromethyl)pyridin-3-yl)methoxy)benzyl)-6-(1- methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

Ex. 3-35-3 3-(3-methoxy-4-((4- (trifluoromethyl)benzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol- 4-yl)-3H-imidazo[4,5- b]pyridin-2-amine

Ex. 3-35-4 3-(4-((6-cyclopropylpyridin-3- yl)methoxy)-3-methoxybenzyl)-6-(1-methyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

Ex. 3-35-5 3-(3-methoxy-4-((2- methylthiazol-4- yl)methoxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H- imidazo[4,5-b]pyridin-2-amine

Ex. 3-36 3-(3-methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-6-phenyl- 3H-imidazo[4,5-b]pyridin-2- amine

Ex. 3-37-1 6-(4-fluorophenyl)-3-(3- methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-3H- imidazo[4,5-b]pyridin-2-amine

Ex. 3-37-2 3-(3-methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-6-(1- methyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-2-amine

Ex. 3-37-3 3-(3-methoxy-4-((6- methoxypyridin-3- yl)methoxy)benzyl)-6-(pyrimidin-5-yl)-3H- imidazo[4,5-b]pyridin-2- amine

Ex. 3-37-4 3-(3-methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-6-(1,3,5- trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

Ex. 3-37-5 3-(3-methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-6-(pyridin- 4-yl)-3H-imidazo[4,5- b]pyridin-2-amine

Ex. 3-37-6 3-(3-methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-6-(pyridin- 3-yl)-3H-imidazo[4,5- b]pyridin-2-amine

Ex. 3-38 3-(3-methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-6-(pyridin- 2-yl)-3H-imidazo[4,5- b]pyridin-2-amine

Ex. 3-39 3-(3-methoxy-4-((4- (perfluoroethyl)benzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol- 4-yl)-3H-imidazo[4,5-b]pyridin- 2-amine

Ex. 3-40-1 3-(3-methoxy-4-((4- (trifluoromethoxy)benzyl)oxy)benzyl)-6-(1-methyl-1H- pyrazol-4-yl)-3H-imidazo[4,5- b]pyridin-2-amine

Ex. 3-40-2 3-(3-methoxy-4-((4- ((trifluoromethyl)thio)benzyl)oxy)benzyl)-6-(1-methyl-1H- pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

Ex. 3-40-3 3-(4-((6-isopropylpyridin-3- yl)methoxy)-3-methoxybenzyl)-6-(1-methyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

Ex. 3-40-4 3-(3-methoxy-4-((4-(2,2,2- trifluoroethyl)benzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol- 4-yl)-3H-imidazo[4,5-b]pyridin- 2-amine

Ex. 3-40-5 3-(3-methoxy-4-((2- (trifluoromethyl)thiazol-4-yl)methoxy)benzyl)-6-(1- methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

Ex. 3-41 6-(cyclohexylethynyl)-3-(3- methoxy-4-((6- methoxypyridin-3-yl)methoxy)benzyl)-3H- imidazo[4,5-b]pyridin-2-amine

Ex. 3-42 4-(2-amino-3-(3-methoxy-4- ((6-methoxypyridin-3-yl)methoxy)benzyl)-3H- imidazo[4,5-b]pyridin-6-yl)but- 3-yn-1-ol

Ex. 3-43 3-(4-(cyclopropyl(6- methoxypyridin-3- yl)methoxy)-3-methoxybenzyl)-6-(1-methyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

Ex. 3-44 3-(3-methoxy-4-((3-methoxy- 5,6,7,8-tetrahydroisoquinolin-8-yl)oxy)benzyl)-6-(1-methyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

Ex. 3-45 1-(1-(3-methoxy-4-((6- methoxypyridin-3-yl)methoxy)phenyl)ethyl)-5-(1- methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine

Ex. 3-46 5-(4-fluorophenyl)-1-(1-(3- methoxy-4-((6- methoxypyridin-3-yl)methoxy)phenyl)ethyl)-1H- benzo[d]imidazol-2-amine

Ex. 3-47 5-(4-fluorophenyl)-1-(1-(3- methoxy-4-((6-(trifluoromethyl)pyridin-3- yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole

Ex. 3-48-1 1-(1-(3-methoxy-4-((6- (trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-5-(1- methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazole

Ex. 3-48-2 4-(1-(1-(3-methoxy-4-((6- (trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1H- benzo[d]imidazol-5-yl)but-3- yn-1-ol

Ex. 3-49 3-(1-(3-methoxy-4-((4- (trifluoromethyl)benzyl)oxy)phenyl)ethyl)-6-(1-methyl-1H- pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

Ex. 3-49-6a 3-(1-(3-methoxy-4-((4- (trifluoromethyl)benzyl)oxy)phenyl)ethyl)-6-(1-methyl-1H- pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine (enantiomer a)

Ex. 3-49-6b 3-(1-(3-methoxy-4-((4- (trifluoromethyl)benzyl)oxy)phenyl)ethyl)-6-(1-methyl-1H- pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine (enantiomer b)

Ex. 3-50-1 2-(4-(2-Amino-3-(1-(3- methoxy-4-((4-(trifluoromethyl)benzyl)oxy) phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1- yl)ethan-1-ol

Ex. 3-50-2 3-(1-(3-Methoxy-4-((4- (trifluoromethyl)benzyl)oxy)phenyl)ethyl)-6-(1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin- 2-amine

Ex. 3-51 3-(1-(3-methoxy-4-((6- (trifluoromethyl)pyridin-3-yl)methoxy)phenyl)propyl)-6- (1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2- amine

Ex. 3-52 3-(1-(3-methoxy-4-((6- (trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-6-(1- methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

Ex. 3-53 3-(1-(3-methoxy-4-((6- (trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-6-(1- methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

Ex. 3-54 2-(4-(2-amino-3-(1-(3- methoxy-4-((6-(trifluoromethyl)pyridin-3- yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-6-yl)- 1H-pyrazol-1-yl)ethan-1-ol

Ex. 3-55 4-(2-amino-3-(1-(3-methoxy-4- ((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H- imidazo[4,5-b]pyridin-6-yl)but- 3-yn-1-ol

Ex. 3-56 4-(3-(4-((6- (difluoromethyl)pyridin-3- yl)methoxy)-3-methoxybenzyl)-3H- imidazo[4,5-b]pyridin-6-yl)but- 3-yn-1-ol

Ex. 3-57 3-(3-methoxy-4-(1-(6- methoxypyridin-3-yl)ethoxy)benzyl)-6-(1-methyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine formate

Ex. 3-58-1 3-(3-methoxy-4-(1-(6- methoxypyridin-3-yl)ethoxy)benzyl)-6-(1-methyl- 1H-pyrazol-5-yl)-3H-imidazo[4,5-b]pyridine formate

Ex. 3-58-2 3-(3-methoxy-4-(1-(6- methoxypyridin-3-yl)ethoxy)benzyl)-6-(6- methoxypyridin-3-yl)-3H- imidazo[4,5-b]pyridineformate

Ex. 3-58-3 6-(2-fluoropyridin-4-yl)-3-(3- methoxy-4-(1-(6-methoxypyridin-3- yl)ethoxy)benzyl)-3H- imidazo[4,5-b]pyridine formate

In one embodiment, the invention relates to a pharmaceutical compositioncomprising Trk inhibitors of Formula (I). In another embodiment of theinvention, the pharmaceutical composition comprising Trk inhibitors ofFormula (I) are administered in an effective amount to achieve thedesired therapeutic effect. The skilled artisan will be able todetermine the effective amount of the pharmaceutical compositioncomprising Trk inhibitors of Formula (I) depending on the individual andthe condition being treated.

In one embodiment of the invention, the Trk inhibitors andpharmaceutical compositions comprising Trk inhibitors can be for use intreating pain. In another embodiment of the invention, the Trkinhibitors and pharmaceutical compositions comprising Trk inhibitors canbe for use in treating pain associated with osteoarthritis. In yetanother embodiment of the invention, the Trk inhibitors andpharmaceutical compositions comprising Trk inhibitors can be for use intreating osteoarthritis.

In one embodiment of the invention, the Trk inhibitors andpharmaceutical compositions comprising Trk inhibitors can be for use ininhibiting tropomyosin-related kinase. In another embodiment of theinvention, the Trk inhibitors and pharmaceutical compositions comprisingTrk inhibitors can be for use in inhibiting TrkA. In another embodimentof the invention, the Trk inhibitors and pharmaceutical compositionscomprising Trk inhibitors can be for use in inhibiting TrkB In yetanother embodiment of the invention, the Trk inhibitors andpharmaceutical compositions comprising Trk inhibitors can be for use ininhibiting TrkC

The Trk inhibitors of the present invention may be administered alone orin a pharmaceutical composition comprising a Trk inhibitor or multipleTrk inhibitors. Suitable pharmaceutical compositions may comprise a Trkinhibitor and one or more pharmaceutically acceptable excipients. Theform in which the Trk inhibitors are administered, for example, powder,tablet, capsule, solution, suspension or emulsion, depends in part onthe route by which it is administered. The Trk inhibitors can beadministered, for example, orally or by injection. Suitable excipientsinclude, but are not limited to, are inorganic or organic materials suchas gelatin, albumin, lactose, starch, stabilizers, melting agents,emulsifying agents, salts and buffers. Suitable pharmaceuticallyacceptable excipients for intra-articular formulations such as solutionsor suspensions include, but are not limited to, commercially availableinert gels or liquids.

The Trk inhibitors and pharmaceutical compositions comprising Trkinhibitors can be administered alone or in combination with one or moreadditional drugs. Additional drugs administered in combination with theTrk inhibitors and pharmaceutical compositions comprising Trk inhibitorsof the present invention include therapies for the treatment of pain andosteoarthritis. The additional drugs may be administered concomitantlywith the Trk inhibitors and pharmaceutical compositions comprising Trkinhibitors. The additional drugs may also be administered in series withthe Trk inhibitors and pharmaceutical compositions comprising Trkinhibitors.

In vitro and in vivo effects of Trk inhibitors and methods of preparingthe preferred Trk inhibitors of the invention are described in theExamples.

EXAMPLES Example 1: In Vitro Studies Example 1-1: TrkA Activity

Reagents and consumables were purchased from Sigma Aldrich, CarnaBiosciences, or Caliper Life Sciences. All assay reaction conditions forIC₅₀ determinations were within the linear range with respect to timeand enzyme concentration. In a 384 well polypropylene plate, TrkA (0.4nM, Carna 08-186) was pre-incubated in a 100 mM Hepes-NaOH pH 7.5 buffercontaining 0.01% Triton X-100, 10 mM MgCl₂, 0.1% BSA, 1 mM DTT, 10 μMsodium orthovanadate and 10 μM beta-glycerophosphate and compound with aconcentration of 2.5% DMSO for 15 minutes at room temperature. Thereaction was initiated with an equal volume of peptide substrate(Caliper Life Sciences catalog no. 760430) and ATP in the aforementionedbuffer. The final concentrations in the reaction were 200 pM TrkA, 1.5μM peptide substrate and 55 μM ATP (ATP Km). The reaction was incubatedat room temperature for 180 minutes and terminated with a buffercontaining excess EDTA (100 mM Hepes-NaOH pH 7.5, 0.02% Brij, 0.1% CR-3,0.36% DMSO and 100 mM EDTA). The plate was run for one cycle on aLabChip 3000 (Caliper Life Sciences, Hopkinton, Mass.) in an off-chipmobility shift type assay with an upstream voltage of −2250 volts, adownstream voltage of −500 volts and a vacuum pressure of −1.6 psi. TheLabChip 3000 separates and measures the fluorescent signal offluorescein labeled peptide substrate and fluorescein labeled peptideproduct present in each well. Results are expressed as percentconversion by measuring peak height for both the substrate and productand dividing the product peak height by the sum of peak heights for bothsubstrate and product. On every plate 100% inhibition (with a saturatingconcentration of staurosporine) and 0% inhibition (substrate with enzymeand DMSO) controls were used to calculate percent inhibition of testedcompounds and a Z′ prime value.

Table 2 displays the TrkA IC₅₀ for selected compounds.

Example 1-2: TrkB Activity

Reagents and consumables were purchased from Sigma Aldrich, CarnaBiosciences, or Caliper Life Sciences. All assay reaction conditions forIC₅₀ determinations were within the linear range with respect to timeand enzyme concentration. In a 384 well polypropylene plate, TrkB (0.6nM, Carna 08-187) was pre-incubated in a 100 mM Hepes-NaOH pH 7.5 buffercontaining 0.01% Triton X-100, 10 mM MgCl₂, 0.1% BSA, 1 mM DTT, 10 uMsodium orthovanadate and 10 μM beta-glycerophosphate and compound with aconcentration of 2.5% DMSO for 15 minutes at room temperature. Thereaction was initiated with an equal volume of peptide substrate(Caliper Life Sciences catalog no. 760430) and ATP in the aforementionedbuffer. The final concentrations in the reaction were 300 pM TrkB, 1.5μM peptide substrate and 70 μM ATP (ATP Km). The reaction was incubatedat room temperature for 180 minutes and terminated with a buffercontaining excess EDTA (100 mM Hepes-NaOH pH 7.5, 0.02% Brij, 0.1% CR-3,0.36% DMSO and 100 mM EDTA). The plate was run for one cycle on aLabChip 3000 (Caliper Life Sciences, Hopkinton, Mass.) in an off-chipmobility shift type assay with an upstream voltage of −2250 volts, adownstream voltage of −500 volts and a vacuum pressure of −1.6 psi. TheLabChip 3000 separates and measures the fluorescent signal offluorescein labeled peptide substrate and fluorescein labeled peptideproduct present in each well. Results are expressed as percentconversion by measuring peak height for both the substrate and productand dividing the product peak height by the sum of peak heights for bothsubstrate and product. On every plate 100% inhibition (with a saturatingconcentration of staurosporine) and 0% inhibition (substrate with enzymeand DMSO) controls were used to calculate percent inhibition of testedcompounds and a Z′ prime value.

Table 2 displays the TrkB IC₅₀ for selected compounds.

Example 1-3: TrkC Activity

Human TrkC, catalytic domain [456-825 (end) amino acids of accessionnumber NP_002521.2] was expressed as N-terminal GST-fusion protein (69kDa) using baculovirus expression system. GST-TRKC was purified by usingglutathione sepharose chromatography and stored in 50 mM Tris-HCl, 150mM NaCl, 0.05% Brij35, 1 mM DTT, 10% glycerol, pH7.5 at −80 C. Thekinase activity was measured by off-chip mobility shift assay. Theenzyme was incubated with fluorecence-labeled substrate, Srctide, in thepresence of 100 uM of ATP (Mg/or Mn)/ATP). The phosphorylated andunphosphorylated substrates were separated and detected by LabChip™3000.

Table 2 displays the TrkC IC₅₀ for selected compounds.

Example 1-4: c-FMS Activity

Reagents and consumables were purchased from Sigma Aldrich, CarnaBiosciences, or Caliper Life Sciences. All assay reaction conditions forIC₅₀ determinations were within the linear range with respect to timeand enzyme concentration. In a 384 well polypropylene plate, c-FMS (0.14nM, Carna 08-155) was pre-incubated in a 100 mM Hepes-NaOH pH 7.5 buffercontaining 0.01% Triton X-100, 10 mM MgCl₂, 0.1% BSA, 1 mM DTT, 10 uMsodium orthovanadate and 10 μM beta-glycerophosphate and compound with aconcentration of 2.5% DMSO for 15 minutes at room temperature. Thereaction was initiated with an equal volume of peptide substrate(Caliper Life Sciences catalog no. 760430) and ATP in the aforementionedbuffer. The final concentrations in the reaction were 70 pM c-FMS, 1.5μM peptide substrate and 500 μM ATP (ATP Km). The reaction was incubatedat room temperature for 120 minutes and terminated with a buffercontaining excess EDTA (100 mM Hepes-NaOH pH 7.5, 0.02% Brij, 0.1% CR-3,0.36% DMSO and 100 mM EDTA). The plate was run for one cycle on aLabChip 3000 (Caliper Life Sciences, Hopkinton, Mass.) in an off-chipmobility shift type assay with an upstream voltage of −2250 volts, adownstream voltage of −500 volts and a vacuum pressure of −1.6 psi. TheLabChip 3000 separates and measures the fluorescent signal offluorescein labeled peptide substrate and fluorescein labeled peptideproduct present in each well. Results are expressed as percentconversion by measuring peak height for both the substrate and productand dividing the product peak height by the sum of peak heights for bothsubstrate and product. On every plate 100% inhibition (with a saturatingconcentration of staurosporine) and 0% inhibition (substrate with enzymeand DMSO) controls were used to calculate percent inhibition of testedcompounds and a Z′ prime value.

Table 2 displays the c-FMS IC₅₀ for selected compounds.

TABLE 2 In vitro Results of Representative Trk Inhibitors [TrkA, TrkBand c-FMS IC₅₀ ] Example IC₅₀ TrkA IC₅₀ TrkB IC₅₀ TrkC IC₅₀ c-FMS No.Compound Name (μM) (μM) (nM) (μM) Ex. 3-11-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)- 0.001 0.0005 — 0.0025-(1-methyl-1H-pyrazol-4-yl)-1H- benzo[d]imidazol-2-amine Ex. 3-2-11-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)- 0.086 0.023 — 0.0045-(pyrimidin-5-yl)-1H-benzo[d]imidazol-2-amine Ex. 3-2-21-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)- 0.008 0.004 — 0.0025-(pyridine-4-yl)-1H-benzo[d]imidazol-2-amine Ex. 3-2-31-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)- 0.003 0.001 — 0.0045-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H- benzo[d]imidazol-2-amineEx. 3-3 (5-(2-Amino-1-(3-methoxy-4-((4- 0.007 0.006 — 0.001methoxybenzyl)oxy)benzyl)-1H- benzo[d]imidazol-5-yl)pyridin-2-yl)dimethylphosphine oxide Ex. 3-4 1-(3-Methoxy-4-((6-methoxypyridin-3-0.836 0.252 — 0.03 yl)methoxy)benzyl)-5-(pyrimidin-5-yl)-1H-benzo[d]imidazole Ex. 3-5 3-(3-methoxy-4-((6-methoxypyridin-3- 0.0060.005 — 0.002 yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine Ex. 3-61-(3-Methoxy-4-((6-methoxypyridin-3- 0.175 0.086 — 0.006yl)methoxy)benzyl)-5-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-benzo[d]imidazol Ex. 3-72-(1-(3-Methoxy-4-((6-methoxypyridin-3- 0.434 0.439 — 0.028yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-5-(piperidin-4-yl)-1,3,4-oxadiazole Ex. 3-81-(3-Methoxy-4-((6-methoxypyridin-3- 11.1 3.46 — 0.359yl)methoxy)benzyl)-5-(piperidin-4-yl)-1H- benzo[d]imidazole Ex. 3-94-(1-(3-Methoxy-4-((6-methoxypyridin-3- 0.793 0.257 — 0.027yl)methoxy)benzyl)-1H-benzo[d]imidazol-5- yl)morpholine Ex. 3-102-(1-(1-(3-Methoxy-4-((6-methoxypyridin-3- 0.652 0.574 — 0.013yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)propan-2-amine Ex. 3-111-(3-methoxy-4-((6-methoxypyridin-3- 0.135 0.12 — 0.012yl)methoxy)benzyl)-5-(2,7-diazaspiro[3.5]nonan-2-yl)-1H-benzo[d]imidazole Ex. 3-121-(1-(3-Methoxy-4-((6-methoxypyridin-3- 1.03 0.637 — 0.031yl)methoxy)benzyl)-1H-benzo[d]imidazol-5- yl)piperidin-4-amine Ex. 3-131-(3-Methoxy-4-((6-methoxypyridin-3- 1.13 0.443 — 0.032yl)methoxy)benzyl)-5-(4-methylpiperazin-1-yl)- 1H-benzo[d]imidazole Ex.3-14 1-(2-Amino-1-(3-methoxy-4-((6-methoxypyridin- 8.98 4.37 — 0.333-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5- yl)-4-methylpiperazin-2-oneEx. 3-15 3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)- 0.0003 0.00010.503 0.002 6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine Ex. 3-16 (5-(2-Amino-3-(3-methoxy-4-((4- 0.0005 0.0002— 0.002 methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-6]pyridin-6-yl)pyridin-2-yl)dimethylphosphine oxide Ex. 3-173-(3-Methoxy-4-((6-methoxypyridin-3- 0.179 0.066 — 0.016yl)methoxy)benzyl)-6-(4-methylpiperazin-1-yl)- 3H-imidazo[4,5-b]pyridineEx. 3-18-1 2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3- 0.054 0.057 —0.005 yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)piperidin-4-yl)propan-2-amine Ex. 3-18-24-(3-(3-Methoxy-4-((6-methoxypyridin-3- 0.09 0.031 — 0.008yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6- yl)morpholine Ex. 3-18-36-(4-Cyclopropylpiperazin-1-yl)-3-(3-methoxy-4- 0.113 0.052 — 0.016((6-methoxypyridin-3-yl)methoxy)benzyl)-3H- imidazo[4,5-b]pyridine Ex.3-18-4 4-(3-(3-Methoxy-4-((6-methoxypyridin-3- 0.47 0.349 — 0.036yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1,4-diazabicyclo[3.2.2]nonane Ex. 3-18-53-(3-Methoxy-4-((6-methoxypyridin-3- 0.025 0.021 — 0.007yl)methoxy)benzyl)-6-(2,7-diazaspiro[3.5]nonan-2-yl)-3H-imidazo[4,5-b]pyridine Ex. 3-18-61-(3-(3-Methoxy-4-((6-methoxypyridin-3- 0.232 0.133 — 0.012yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6- yl)piperidin-4-amine Ex.3-18-7 (S)-1-(3-(3-Methoxy-4-((6-methoxypyridin-3- 0.008 0.013 — 0.032yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyrrolidine-2-carboxylicacid Ex. 3-193-(3-Methoxy-4-((6-methoxypyridin-3- 0.001 0.0009 — 0.002yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine Ex. 3-203-(3-Methoxy-4-((6-methylpyridin-3- 0.0009 0.0006 — 0.003yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine Ex. 3-213-(3-(3-Methoxy-4-((6-methoxypyridin-3- 0.026 0.024 — 0.007yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazole Ex. 3-223-(1-(3-Methoxy-4-((6-methoxypyridin-3- 0.306 0.317 — 0.015yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazole Ex. 3-232-(3-(3-Methoxy-4-((6-methoxypyridin-3- 0.051 0.057 — 0.013yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,3,4-oxadiazole Ex. 3-242-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3- 0.088 0.043 — 0.007yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-1,2,3-triazol-4-yl)propan-2-amine Ex. 3-253-(3-Methoxy-4-((6-methoxypyridin-3- 0.032 0.018 — 0.003yl)methoxy)benzyl)-6-(4-(piperidin-3-yl)-1H-l,2,3-triazol-1-yl)-3H-imidazo[4,5-b]pyridine Ex. 3-261-(3-methoxy-4-((6-methoxypyridin-3- 0.59 0.315 — 0.03yl)methoxy)benzyl)-5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-amine Ex. 3-271-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3- 0.852 0.305 — 0.379yl)methoxy)benzyl)-5-(4-methylpiperazin-1-yl)- 1H-benzo[d]imidazole Ex.3-28 3-(3-Ethoxy-4-((6-methoxypyridin-3- 0.337 0.179 — 0.012yl)methoxy)benzyl)-6-(4-methylpiperazin-1-yl)- 3H-imidazo[4,5-b]pyridineEx. 3-29 1-(1-(3-Methoxy-4-((6-methoxypyridin-3- 6.02 4.28 — 0.431yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)- 4-methylpiperazin-2-oneEx. 3-30 3-(3-Methoxy-4-((6-methoxypyridin-3- 0.201 0.118 — 0.015yl)methoxy)benzyl)-6-(5-methyl-1-azabicyclo[3.2.1]oct-6-en-7-yl)-3H-imidazo[4,5- b]pyridine Ex. 3-311-(3-methoxy-4-((6-methoxypyridin-3- 1.48 0.889 — 0.161yl)methoxy)benzyl)-5-(5-methyl-1- azabicyclo[3.2.1]oct-6-en-7-yl)-1H-benzo[d]imidazole Ex. 3-32 7-(3-(3-methoxy-4-((6-methoxypyridin-3- 0.360.15 — 0.041 yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1-azabicyclo[3.2.1]oct-6-en-5-ol Ex. 3-337-(1-(3-Methoxy-4-((6-methoxypyridin-3- 1.16 0.372 — 0.151yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-1-azabicyclo[3.2.1]oct-6-en-5-ol Ex. 3-343-(3-methoxy-4-(1-(6-methoxypyridin-3- 0.032 0.026 — 0.059yl)propoxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine Ex. 3-35-13-(3-methoxy-4-((6-methoxypyridin-3- 0.0006 0.0003 — 0.003yl)methoxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine Ex. 3-35-23-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3- 0.0002 0.0002 — 0.005yl)methoxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine Ex. 3-35-3 3-(3-methoxy-4-((4-0.0002 0.0003 — 0.005 (trifluoromethyl)benzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2- amine Ex. 3-35-43-(4-((6-cyclopropylpyridin-3-yl)methoxy)-3- 0.0002 0.0002 — 0.003methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine Ex. 3-35-53-(3-methoxy-4-((2-methylthiazol-4- 0.0005 0.0002 — 0.005yl)methoxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine Ex. 3-363-(3-methoxy-4-((6-methoxypyridin-3- 0.006 0.004 — 0.007yl)methoxy)benzyl)-6-phenyl-3H-imidazo[4,5- b]pyridin-2-amine Ex. 3-37-16-(4-fluorophenyl)-3-(3-methoxy-4-((6- 0.009 0.004 — 0.009methoxypyridin-3-yl)methoxy)benzyl)-3H- imidazo[4,5-b]pyridin-2-amineEx. 3-37-2 3-(3-methoxy-4-((6-methoxypyridin-3- 0.003 0.002 — 0.005yl)methoxy)benzyl)-6-(1-methyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-2-amine Ex. 3-37-33-(3-methoxy-4-((6-methoxypyridin-3- 0.051 0.016 — 0.011yl)methoxy)benzyl)-6-(pyrimidin-5-yl)-3H- imidazo[4,5-b]pyridin-2-amineEx. 3-37-4 3-(3-methoxy-4-((6-methoxypyridin-3- 0.014 0.013 — 0.005yl)methoxy)benzyl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine Ex. 3-37-53-(3-methoxy-4-((6-methoxypyridin-3- 0.002 0.0007 — 0.002yl)methoxy)benzyl)-6-(pyridin-4-yl)-3H- imidazo[4,5-b]pyridin-2-amineEx. 3-37-6 3-(3-methoxy-4-((6-methoxypyridin-3- 0.005 0.002 — 0.006yl)methoxy)benzyl)-6-(pyridin-3-yl)-3H- imidazo[4,5-b]pyridin-2-amineEx. 3-38 3-(3-methoxy-4-((6-methoxypyridin-3- 0.004 0.002 — 0.005yl)methoxy)benzyl)-6-(pyridin-2-yl)-3H- imidazo[4,5-b]pyridin-2-amineEx. 3-39 3-(3-methoxy-4-((4- 0.0003 0.0006 — 0.028(perfluoroethyl)benzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2- amine Ex. 3-40-13-(3-methoxy-4-((4- 0.0002 0.0002 — 0.008(trifluoromethoxy)benzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5- b]pyridin-2-amine Ex. 3-40-23-(3-methoxy-4-((4- 0.0002 0.0006 — 0.018((trifluoromethyl)thio)benzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5- b]pyridin-2-amine Ex. 3-40-33-(4-((6-isopropylpyridin-3-yl)methoxy)-3- 0.0002 0.0002 — 0.005methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine Ex. 3-40-4 3-(3-methoxy-4-((4-(2,2,2-0.0002 0.0003 — 0.01 trifluoroethyl)benzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2- amine Ex. 3-40-53-(3-methoxy-4-((2-(trifluoromethyl)thiazol-4- 0.0002 0.0002 — 0.007yl)methoxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine Ex. 3-416-(cyclohexylethynyl)-3-(3-methoxy-4-((6- 0.065 0.08 — 0.213methoxypyridin-3-yl)methoxy)benzyl)-3H- imidazo[4,5-b]pyridin-2-amineEx. 3-42 4-(2-amino-3-(3-methoxy-4-((6-methoxypyridin- 0.007 0.003 —0.013 3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin- 6-yl)but-3-yn-1-olEx. 3-43 3-(4-(cyclopropyl(6-methoxypyridin-3- 0.058 0.051 — 0.794yl)methoxy)-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine Ex. 3-443-(3-methoxy-4-((3-methoxy-5,6,7,8- 0.039 0.041 — 0.765tetrahydroisoquinolin-8-yl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5- b]pyridin-2-amine Ex. 3-451-(1-(3-methoxy-4-((6-methoxypyridin-3- 0.003 0.001 — 0.073yl)methoxy)phenyl)ethyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine Ex. 3-465-(4-fluorophenyl)-1-(1-(3-methoxy-4-((6- 0.085 0.037 — 0.686methoxypyridin-3-yl)methoxy)phenyl)ethyl)-1H- benzo[d]imidazol-2-amineEx. 3-47 5-(4-fluorophenyl)-1-(1-(3-methoxy-4-((6- 1.24 0.427 — 4.13(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole Ex. 3-48-11-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin- 0.102 0.014 — 0.163-yl)methoxy)phenyl)ethyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazole Ex. 3-48-2 4-(1-(1-(3-methoxy-4-((6-0.692 0.127 — 4.68 (trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazol- 5-yl)but-3-yn-1-ol Ex.3-49 3-(1-(3-methoxy-4-((4- n/d n/d — n/d(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5- b]pyridin-2-amine Ex. 3-49-6a3-(1-(3-methoxy-4-((4- 0.0003 0.0006 — 0.019(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5- b]pyridin-2-amine (enantiomer a)Ex. 3-49-6b 3-(1-(3-methoxy-4-((4- 0.005 0.003 — 0.096(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5- b]pyridin-2-amine (enantiomer b)Ex. 3-50-1 2-(4-(2-Amino-3-(1-(3-methoxy-4-((4- n/d n/d — n/d(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1- yl)ethan-1-ol Ex. 3-50-23-(1-(3-Methoxy-4-((4- n/d n/d — n/d(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-6-(1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine Ex. 3-513-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin- n/d n/d — n/d3-yl)methoxy)phenyl)propyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine Ex. 3-523-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin- 0.007 0.001 — 0.0563-yl)methoxy)phenyl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine Ex. 3-533-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin- 0.0004 0.0006 — 0.0193-yl)methoxy)phenyl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine Ex. 3-542-(4-(2-amino-3-(1-(3-methoxy-4-((6- n/d n/d — n/d(trifluoromethyl)pyridin-3- yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)ethan-1-ol Ex. 3-554-(2-amino-3-(1-(3-methoxy-4-((6- 0.001 0.001 — 0.137(trifluoromethyl)pyridin-3- yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-6-yl)but-3-yn-1-ol Ex. 3-564-(3-(4-((6-(difluoromethyl)pyridin-3- 0.017 0.004 — 0.025yl)methoxy)-3-methoxybenyl)-3H-imidazo[4,5- b]pyridin-6-yl)but-3-yn-1-olEx. 3-57 3-(3-methoxy-4-(1-(6-methoxypyridin-3- 0.035 0.013 — 0.058yl)ethoxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine formate Ex. 3-58-13-(3-methoxy-4-(1-(6-methoxypyridin-3- 0.449 0.219 — 0.082yl)ethoxy)benzyl)-6-(1-methyl-1H-pyrazol-5-yl)-3H-imidazo[4,5-b]pyridine formate Ex. 3-58-23-(3-methoxy-4-(1-(6-methoxypyridin-3- 0.16 0.61 — 0.103yl)ethoxy)benzyl)-6-(6-methoxypyridin-3-yl)-3H- imidazo[4,5-b]pyridineformate Ex. 3-58-3 6-(2-fluoropyridin-4-yl)-3-(3-methoxy-4-(1-(6- 0.2150.068 — 0.102 methoxypyridin-3-yl)ethoxy)benzyl)-3H-imidazo[4,5-b]pyridine formate n/d indicates none detected — indicatesnot tested

Example 2: In Vivo Studies Example 2-1: Effect of Trk Inhibitors onReactivated Peptidoglycan-Polysaccharide Knee Arthritis

Male Lewis rats were acclimated to the testing facility for 7 days. Therats were housed in 5 per cage in shoe-box polycarbonate cages with wiretops, wood chip bedding and suspended food and water bottles.

On day −21, the male Lewis rats were randomized into treatment groups bybody weight. The rats were anesthetized and injected withpeptidoglycan-polysaccharide (PGPS) into the right knee to induce PGPSarthritis. Arthritis was reactivated on days 0 and 14 by an IV tailinjection of PGPS. The animals were dosed intra-articularly withvehicle, triamcinolone and test compound on day −7. The treatment groupsare presented in Table 3 below.

TABLE 3 PGPS Knee Arthritis Treatment Groups Group Treatment Dose 1Vehicle N/A (No reactivation) 2 Vehicle N/A 3 Triamcinolone 0.06 mg 43-(3-Methoxy-4-((4- 1 mg methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H- imidazo[4,5-b]pyridin-2-amine

The rats were weighed at baseline on days 0, 4, 14 and 18. Kneethickness was measured by caliper at baseline and on days 0, 2, 4, 14,16 and 18. Gait analysis occurred on days 0-4 and 14-18, with videorecording of selected animals on days 3 and 17. Gait analysis wasperformed by applying ink to the ventral surface of the foot anddocumenting weight bearing during movement across paper.

The animals were terminated at day 18. Right knees were removed, trimmedof extraneous tissue, and collected into 10% neutral buffered formalin.After two days in the formalin buffer and three days in 10% formic aciddecalcifier, the knees were cut into two approximately equal halves inthe frontal plane and processed for paraffin embedding and stained withT. Blue. Histological examinations were subsequently performed for boneresorption, inflammation, pannus and cartilage damage.

Body weights, gait deficiency and caliper measurements were analyzedusing a one-way analysis of variance (1-way ANOVA) with Dunnett'smultiple comparison post-test. Gait scores were analyzed using aKruskal-Wallis test (non-parametric ANOVA) with Dunn's multiplecomparison post-test. Histopathology scores were analyzed using aKruskal-Wallis test (non-parametric ANOVA) with Dunn's multiplecomparison post-test.

Vehicle control animals gained an average of approximately 96 grams ofbody weight over the course of the study, which was a significantreduction from the non-reactivated controls. There were no significantdifferences compared to any of the treatment groups. Following thesecond reactivation, several animals developed systemic PGPSinflammation that affected the ankles and compromised the painmeasurement. Gait scores and deficiency for the vehicle controls peakedtwo days after the first reactivation and one day after the secondreactivation, and were significantly increased over the non-reactivatedcontrols at all time points except for the two pre-reactivation timepoints (days 0 and 14). The first reactivation peaked higher, butdropped off more sharply. The pattern was reversed for knee calipermeasurements, with a much higher peak and sharper drop-off after thesecond reactivation. Histopathology sections had marked to severeinflammation with minimal to mild pannus and cartilage damage andminimal to moderate bone resorption. All parameters were significantlyincreased over the non-reactivated controls, which had minimal lesions,except for bone resorption, which ranged from minimal to marked.

Animals treated with 0.06 mg of Triamcinolone had significantly reducedgait scores and deficiency throughout the first reactivation (days 1-4)and on day 15, 17, and 18 of the second reactivation. AUC values werealso significantly reduced, whether each reactivation was calculatedseparately (74-99%) or summed (88-92%). Knee caliper measurements weresignificantly reduced on days 2, 4, 16, and 18, as well as prior to thefirst reactivation on day 0, with corresponding 53-106% reductions inthe AUC. Histopathology sections had significant 61-88% reductions inall parameters, with a significant 74% reduction in summed scores.

Animals treated with 1 mg of3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-aminehad significant reductions in gait scores and deficiency throughout thefirst reactivation. Scores were significantly reduced throughout thesecond reactivation, and reductions in deficiency were significant ondays 15, 17, and 18. AUC values for the first (92-93%) and second(85-86%) reactivations were significantly reduced for both scores anddeficiency, and the summed AUC was significantly reduced for deficiency(84%). Knee caliper measurements were significantly reduced on day 14(just prior to the second reactivation). AUC values were generallyunaffected by treatment. Histopathology sections had significant 49-94%reductions in all parameters, with a significant 70% reduction in summedscores.

Example 2-2: Effect of Trk Inhibitors on Monosodium Iodoacetate InducedOsteoarthritis

Male Wistar rats were acclimated to the testing facility for 5 days. Therats were individually housed in micro-isolator shoe-box polycarbonatecages with cob bedding and water bottles. Dry pelleted food of knowncomposition and nutritional components was provided ad libitum

Animals were randomized by treatment type using an online random numbergenerator. Each treatment group was assigned a number, entered into therandom number generator, recorded then translated back to the associatedtreatment. All injections were given in the left leg unless thetreatment indicated “Contralateral” in which case the injection wasgiven in the right leg. Both legs were shaved on all animals at the timeof the treatment injections to blind the test administrator.

The rats were weighed the day prior to injection with monosodiumiodoacetate (MIA), the agent used to induce osteoarthritis in theanimals. The day of injection, rats from groups 2-8 received asubcutaneous (SC) dose of buprenorphine at least one hour prior toinduction. Anesthesia induction was achieved for all groups. Naïveanimals were then placed in recovery. All other animals received aninjection of MIA. In animals receiving MIA, the hind leg was flexed andan injection of MIA (25 μL) was injected into the intra-articular spaceusing a 27 gauge ½ Inch Needle. Standard postoperative care wasperformed (twice daily for 48 hours).

Group Treatment Animals/Group Animals/Time Point 1 Naïve 8 8 2 MIA/LRS*8 8 3 MIA/3-(3-Methoxy-4-((4- 8 8 methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H- imidazo[4,5-b]pyridin-2-amine (100 μg)Ipsilateral 4 MIA/3-(3-Methoxy-4-((4- 8 8methoxybenzyl)oxy)benzyl)-6-(1- methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine (100 μg) Contralateral 5MIA/3-(3-Methoxy-4-((4- 8 8 methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H- imidazo[4,5-b]pyridin-2-amine (30 μg)Ipsilateral 6 MIA/3-(3-Methoxy-4-((4- 8 8methoxybenzyl)oxy)benzyl)-6-(1- methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine (30 μg) Contralateral 7MIA/3-(3-Methoxy-4-((4- 8 8 methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H- imidazo[4,5-b]pyridin-2-amine (10 μg)Ipsilateral 8 MIA/3-(3-Methoxy-4-((4- 8 8methoxybenzyl)oxy)benzyl)-6-(1- methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine (10 μg) Contralateral *Lactated Ringer'sSolution: injection control/placebo.

On Day 8 the test article was administered as described above. On Days−1, 7, 14, 21, 28, and 35 post-induction, weight bearing was assessed. Aweight bearing scale was utilized using a plexiglass chamber to assessthe amount of weight distributed in each hind limb. The animals wereacclimated to the chamber for at least 5 minutes prior to testing andthe weight distribution was recorded 5 times.

No adverse observations were found in body weight results due totreatment. MIA/LRS was significantly worse thanMA/3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amineIpsilateral 100 μg and 30 μg at day 35 (p<0.05).

3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine100 and 30 μg Ispilateral injections were effective throughout the fourweeks following administration. The3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine10 μg Ipsilateral efficacy was observed at 2 through 4 weeks followingadministration.3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine100 μg Contralateral did not show systemic pain relief at any timepointthroughout the study (1-4 weeks), whereas3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine30 μg Contralateral administration resulted in efficacy at only the 3week timepoint and3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine10 μg Contralateral administration resulted in efficacy at 3 and 4 weeksfollowing administration.

The animals were terminated at day 36. Both stifles were collected fromeach animal; the skin was removed from the joint and the patella wasremoved while leaving as much of the fat pad intact with the joint. Thestifle was placed in the appropriate cassette with rolled gauze tosecure the stifle in the cassette and then placed into 4%Paraformaldehyde. These samples were examined histologically.Histopathology revealed no adverse changes attributable to3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-aminein the knee joint.

Example 3: Synthesis of Trk Inhibitors Example 3-1: Synthesis of1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amineExample 3-1-1: Preparation of3-Methoxy-4-((4-methoxybenzyl)oxy)benzonitrile

To a stirred solution of 4-hydroxy-3-methoxybenzonitrile (2.43 g, 16.29mmol) in acetonitrile (75 mL) was added cesium carbonate (6.68 g, 20.50mmol) and p-methoxybenzyl chloride (2.81 g, 17.92 mmol). The reactionmixture was heated to reflux and stirred. After 1 h, the mixture wasallowed to cool to room temperature and was filtered. The filtrate wasconcentrated to provide 4.56 g (>100%)3-methoxy-4-((4-methoxybenzyl)oxy)benzonitrile as an off-white solid.The crude material was used without purification in the next reaction.

Example 3-1-2: Preparation of(3-Methoxy-4-((4-methoxybenzyl)oxy)phenyl)methanamine

To a stirred solution of crude3-methoxy-4-((4-methoxybenzyl)oxy)benzonitrile (4.39 g, 16.29 mmol) intetrahydrofuran (50 mL) was added lithium aluminum hydride (0.93 g,24.44 mmol Caution: gas evolution and moderate exotherm). The resultingmixture was allowed to stir at room temperature. After 1 h, the reactionmixture was cooled to 0° C. while water (930 μL) was added slowly (gasevolution). The mixture was then treated with 1N sodium hydroxidesolution (930 μL) and additional water (2.8 mL). The mixture was allowedto stir for 15 min, and then it was filtered through Celite with the aidof ethyl acetate. The filtrate was dried over magnesium sulfate,filtered, and concentrated to provide 3.90 g (86% for 2 steps) of3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)methanamine as an off-whitesolid.

Example 3-1-3: Preparation of4-bromo-N-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-2-nitroaniline

To a stirred solution of3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)methanamine (4.48 g, 16.39mmol) in acetonitrile (75 mL) was added 4-bromo-1-fluoro-2-nitrobenzene(3.43 g, 15.61 mmol) and diisopropylethylamine (2.52 g, 19.51 mmol). Theresulting bright yellow solution was heated to reflux. After 16 h, theorange mixture was allowed to cool to room temperature and was dilutedwith water. The mixture was extracted with dichloromethane (2×150 mL).The combined organic phases were dried over magnesium sulfate, filtered,and concentrated to provide 7.71 g (99%) of4-bromo-N-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-2-nitroaniline asan orange semi-solid.

Example 3-1-4: Preparation of4-bromo-N¹-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)benzene-1,2-diamine

To a stirred suspension of4-bromo-N-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-2-nitroaniline(7.71 g, 16.30 mmol) in tetrahydrofuran (100 mL), ethanol (25 mL), andwater (25 mL) was added ammonium chloride (0.44 g, 8.15 mmol) and ironpowder (9.10 g, 163 mmol). The mixture was heated to reflux. After 5 h,the reaction mixture was allowed to cool to room temperature and wasfiltered through Celite with the aid of ethanol. The filtrate wasconcentrated, and the residue partitioned between dichloromethane andwater. The organic phase was separated, dried over magnesium sulfate,filtered, and concentrated to provide 6.73 g (95%) of4-bromo-N¹-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)benzene-1,2-diamineas a brown solid.

Example 3-1-5: Preparation of5-bromo-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-2-amine

To a stirred solution of cyanogen bromide (5.0 M in acetonitrile, 5.0mL, 25.0 mmol) in water (75 mL) was added a solution of4-bromo-N-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)benzene-1,2-diamine(3.40 g, 7.67 mmol) in methanol (75 mL), acetonitrile (75 mL), anddichloromethane (25 mL). The addition of the diamine solution wasconducted over 45 min. The resulting brown solution was allowed to stirat room temperature. After 16 h, the reaction mixture was concentrated,and the residue was dissolved in dichloromethane. The solution waswashed with 1N sodium hydroxide solution, dried over magnesium sulfate,filtered, and concentrated to provide 2.46 g of an orange-brown solid.Trituration of the crude material with diethyl ether afforded 1.54 g of5-bromo-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-2-amineas an off-white solid.

Example 3-1-6: Preparation of1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine

To a stirred suspension of5-bromo-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-2-amine(0.28 g, 0.59 mmol) in 1,4-dioxane (8 mL) and water (6 mL) was added1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.15 g, 0.73 mmol), potassium phosphate (0.44 g, 2.06 mmol),tricyclohexylphosphine (0.016 g, 0.059 mmol), and palladium(II)acetate(0.007 g, 0.029 mmol). The reaction mixture was heated to 125° C. in amicrowave reactor. After 15 min, the reaction mixture was diluted withwater. The mixture was extracted with ethyl acetate (×3), and thecombined organic phases were washed with brine, dried over magnesiumsulfate, filtered, and concentrated to provide 0.33 g of a light greensolid. Chromatographic purification (Combi-Flash, 12 g SiO₂ gold column,1-5% 2 M ammonia in methanol/dichloromethane elute) afforded 0.13 g(48%) of the product as an off-white solid: ¹H NMR (400 MHz, DMSO-d6) δ7.96 (s, 1H), 7.71 (s, 1H), 7.34-7.24 (m, 3H), 7.05-6.87 (m, 6H),6.65-6.60 (m, 1H), 6.50 (s, 2H), 5.11 (s, 2H), 4.90 (s, 2H), 3.81 (s,3H), 3.72 (s, 3H), 3.69 (s, 3H) ppm; (M+1) 470.

Example 3-2: Synthesis of Additional Compounds from5-bromo-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-2-amine

The following compounds were prepared using the procedure described inExample 3-1 by employing the appropriate boronic acid/boronate estercoupling partner:

Example 3-2-1:1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyrimidin-5-yl)-1H-benzo[d]imidazol-2-amine

¹H NMR (400 MHz, DMSO-d6) δ 9.09-9.07 (m, 3H), 7.57-7.54 (m, 1H),7.34-7.30 (m, 2H), 7.28-7.20 (m, 2H), 7.01 (d, J=1.9 Hz, 1H), 6.98-6.89(m, 3H), 6.71 (br s, 2H), 6.66 (dd, J=8.3, 1.9 Hz, 1H), 5.20 (s, 2H),4.93 (s, 2H), 3.74 (s, 3H), 3.72 (s, 3H) ppm; (M+1) 468.

Example 3-2-2:1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyridine-4-yl)-1H-benzo[d]imidazol-2-amine

¹H NMR (400 MHz, DMSO-d6) δ 8.54 (dd, J=4.6, 1.5 Hz, 2H), 7.66 (dd,J=4.6, 1.6 Hz, 2H), 7.56 (d, J=1.4 Hz, 1H), 7.36-7.27 (m, 3H), 7.21 (d,J=8.2 Hz, 1H), 7.01 (d, J=1.8 Hz, 1H), 6.98-6.88 (m, 3H), 6.72-6.64 (m,3H), 5.20 (s, 2H), 4.93 (s, 2H), 3.74 (s, 3H), 3.72 (s, 3H) ppm; (M+1)467.

Example 3-2-3:1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine

¹H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.74 (s, 1H), 7.36-7.27 (m,3H), 7.07-7.01 (m, 2H), 6.98 (d, J=1.9 Hz, 1H), 6.96-6.89 (m, 3H), 6.65(dd, J=8.3, 1.9 Hz, 1H), 6.54 (br s, 2H), 5.14 (s, 2H), 4.92 (s, 2H),4.20 (t, J=6.6 Hz, 2H), 3.74 (s, 3H), 3.71 (s, 3H), 3.59-3.50 (m, 4H),2.72 (t, J=6.6 Hz, 2H), 2.44-2.36 (m, 4H) ppm; (M+1) 569.

Example 3-3: Synthesis of(5-(2-Amino-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-5-yl)pyridin-2-yl)dimethylphosphineoxide Example 3-3-1: Preparation of4-iodo-N-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-2-nitroaniline

To a stirred solution of3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)methanamine (5.02 g, 18.37mmol) in acetonitrile (75 mL) was added 1-fluoro-4-iodo-2-nitrobenzene(4.67 g, 17.49 mmol) and diisopropylethylamine (2.83 g, 21.86 mmol). Theresulting bright yellow solution was heated to reflux. After 17 h, theorange mixture was allowed to cool to room temperature and was dilutedwith water. The mixture was extracted with dichloromethane (3×100 mL).The combined organic phases were dried over magnesium sulfate, filtered,and concentrated to provide 9.49 g (>100%) of4-iodo-N-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-2-nitroaniline as anorange semi-solid.

Example 3-3-2: Preparation of4-iodo-N¹-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)benzene-1,2-diamine

To a stirred solution of4-iodo-N-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-2-nitroaniline (9.10g, 17.49 mmol) in tetrahydrofuran (50 mL), ethanol (50 mL), and water(10 mL) was added ammonium chloride (7.48 g, 139.9 mmol) and iron (II)sulfate heptahydrate (14.59 g, 52.47 mmol). The bright orange suspensionwas treated with zinc (3.43 g, 52.47 mmol). The mixture was graduallywarmed to reflux. After 3.5 h, the color of the reaction mixture hadturned from orange to olive-green. At this point the reaction mixturewas allowed to cool to room temperature. The mixture was filteredthrough Celite, and the filtercake was washed with methanol. Thefiltrate concentrated, the residue was suspended in water. The aqueousmixture was extracted with chloroform (×3). The combined organic phaseswere dried over magnesium sulfate, filtered, and concentrated to afford8.32 g (97%) of4-iodo-N¹-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)benzene-1,2-diamineas a tan solid.

Example 3-3-3: Preparation of5-iodo-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-2-amine

To a stirred suspension of4-iodo-N¹-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)benzene-1,2-diamine(8.32 g, 16.97 mmol) in dichloromethane (100 mL) and methanol (50 mL)was added cyanogen bromide solution (5.0 M in acetonitrile, 17.0 mL,85.00 mmol). The resulting brown reaction mixture was allowed to stir atroom temperature. After 16 h, the mixture was treated with 1 N sodiumhydroxide solution (250 mL) and was allowed to stir at room temperature.After 15 min, a precipitate formed. The solids were isolated byfiltration, washed with water, and dried to afford 4.42 g (51%) of5-iodo-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-2-amineas a tan solid.

Example 3-3-4: Preparation of5-(6-chloropyridin-3-yl)-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-2-amine

To a stirred suspension of5-iodo-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-2-amine(0.40 g, 0.78 mmol) in 1,4-dioxane (10 mL) and water (4 mL) was added(6-chloropyridin-3-yl)boronic acid (0.14 g, 0.89 mmol), potassiumphosphate (0.58 g, 2.72 mmol), tricyclohexylphosphine (0.044 g, 0.16mmol), and palladium(II)acetate (0.017 g, 0.078 mmol). The reactionmixture was heated to 125° C. in a microwave reactor. After 15 min, thereaction mixture was diluted with water. The mixture was extracted withchloroform (×3). The combined organic phases were dried over magnesiumsulfate, filtered, and concentrated to provide 0.43 g of a brown solid.Chromatographic purification (Combi-Flash, 24 g SiO₂ gold column, 5-10%methanol/dichloromethane elute) afforded 0.23 g (58%) of5-(6-chloropyridin-3-yl)-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-2-amineas a light yellow solid.

Example 3-3-5: Preparation of(5-(2-Amino-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-5-yl)pyridin-2-yl)dimethylphosphineoxide

To a stirred suspension of5-(6-chloropyridin-3-yl)-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-2-amine(0.15 g, 0.30 mmol) in 1,4-dioxane (4 mL) was added dimethylphosphineoxide (0.029 g, 0.37 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.035 g, 0.060 mmol),palladium(II) acetate (0.007 g, 0.030 mmol), and cesium carbonate (0.20g, 0.60 mmol). The reaction mixture was heated to 150° C. in a microwavereactor. After 45 min, additional portions of dimethylphosphine oxide(0.029 g, 0.37 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene(0.035 g, 0.060 mmol), and palladium(II) acetate (0.007 g, 0.030 mmol)were added. The reaction mixture was subjected to a second round ofheating in the microwave reactor (45 min, 150° C.). After the secondheating cycle, the reaction mixture was diluted with water and wasextracted with chloroform (×3). The combined organic phases were driedover magnesium sulfate, filtered, and concentrated to provide 0.24 g ofa bright yellow solid. Chromatographic purification (Combi-Flash, 12 gSiO2 gold column, 5-10% 2M ammonia in methanol/dichloromethane elute)afforded 0.052 g (32%) of the product as a yellow solid: ¹H NMR (400MHz, DMSO-d6) δ ¹H NMR (400 MHz, DMSO) δ 9.03 (d, J=1.9 Hz, 1H),8.22-8.14 (m, 1H), 7.95 (dd, J=8.2, 4.9 Hz, 1H), 7.52 (s, 1H), 7.32 (d,J=8.6 Hz, 2H), 7.28-7.19 (m, 2H), 7.02 (d, J=1.9 Hz, 1H), 6.96 (d, J=8.2Hz, 1H), 6.91 (d, J=8.6 Hz, 2H), 6.71-6.64 (m, 3H), 5.20 (s, 2H), 4.93(s, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 1.68 (d, J=13.5 Hz, 6H) ppm;(M+1)=543.

Example 3-4: Synthesis of1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(pyrimidin-5-yl)-1H-benzo[d]imidazoleExample 3-4-1: Preparation of tert-butyl3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzylcarbamate

To a stirred solution of tert-butyl 4-hydroxy-3-methoxybenzylcarbamate(22.44 g, 88.59 mmol) in acetonitrile (250 mL) was added potassiumcarbonate (30.61 g, 221.5 mmol) and 5-(chloromethyl)-2-methoxypyridinehydrochloride (18.33 g, 94.46 mmol). The resulting mixture was heated toreflux and stirred. After 23 h, the light green suspension was allowedto cool to room temperature and was diluted with water (600 mL),resulting in the formation of a precipitate. The solids were isolated byfiltration and washed with water. The moist solids were dissolved indichloromethane (300 mL), and a small amount of water separated and wasremoved. The organic phase was dried over magnesium sulfate, filtered,and concentrated to provide 31.92 g (96%) of tert-butyl3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzylcarbamate as anoff-white solid.

Example 3-4-2: Preparation of(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine

To a stirred solution of tert-butyl3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzylcarbamate (31.92 g,85.25 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid(75 mL, 973.5 mmol). The resulting yellow solution was allowed to stirat room temperature. After 2 h, the reaction mixture was concentrated todryness, and the residue was dissolved in water (250 mL). The acidicsolution was extracted with diethyl ether (2×125 mL; organic phasesdiscarded). The aqueous phase was then made basic with concentratedammonium hydroxide. The basic aqueous phase was then extracted withdichloromethane (2×200 mL). The combined organic phases were dried overmagnesium sulfate, filtered, and concentrated to provide 21.46 g (92%)of (3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine as anoff-white solid.

Example 3-4-3: Preparation of4-iodo-N-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-2-nitroaniline

To a stirred solution of(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine (5.00 g,18.23 mmol) in acetonitrile (75 mL) was added1-fluoro-4-iodo-2-nitrobenzene (4.55 g, 17.04 mmol) anddiisopropylethylamine (3.30 g, 25.56 mmol). The yellow solution washeated to reflux and stirred. After 4 h, the orange-brown mixture wasallowed to cool to room temperature and was diluted with water (150 mL).The resulting bright orange precipitate was isolated by filtration andwashed with water. The moist solids were dissolved in dichloromethane,and a small amount of water separated and was removed. The organic phasewas dried over magnesium sulfate, filtered, and concentrated to provide7.10 g (80%) of4-iodo-N-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-2-nitroanilineas a bright orange solid.

Example 3-4-4: Preparation of4-iodo-N¹-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)benzene-1,2-diamine

To a stirred solution of4-iodo-N-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-2-nitroaniline(7.10 g, 13.62 mmol) in tetrahydrofuran (100 mL), methanol (50 mL), andwater (10 mL) was added ammonium chloride (5.83 g, 109.0 mmol) and iron(II) sulfate heptahydrate (13.25 g, 47.67 mmol). The bright orangesuspension was treated with zinc (3.12 g, 47.67 mmol). The mixture wasgradually warmed to reflux. After 20 min, the color of the reactionmixture had turned from orange to ollie-green. At this point thereaction mixture was allowed to cool to room temperature. The mixturewas filtered through Celite, and the filtercake was washed withchloroform. The filtrate was then washed with 5N ammonium hydroxidesolution (75 mL). The organic phase was dried over magnesium sulfate,filtered, and concentrated to provide 6.49 g of4-iodo-N¹-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)benzene-1,2-diamineas a tan solid.

Example 3-4-5: Preparation of5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole

To a stirred suspension of4-iodo-N-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)benzene-1,2-diaminein ethanol (100 mL) was added triethyl orthoformate (4.45 g, 30.03 mmol)and p-toluenesulfonic acid monohydrate (0.075 g, 0.39 mmol). As theresulting mixture was warmed to reflux, the solids gradually dissolvedto provide an orange solution. After 45 min, the reaction mixture wasallowed to cool to room temperature, resulting in the formation of aprecipitate. Water (250 mL) was added to the mixture, and the solidswere isolated by filtration. The moist solids were dissolved in ethylacetate (250 mL), and this solution was washed with brine, dried overmagnesium sulfate, filtered, and concentrated to provide 5.99 g (91%) of5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazoleas a tan solid.

Example 3-4-6: Preparation of1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(pyrimidin-5-yl)-1H-benzo[d]imidazole

To a suspension of5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole(0.37 g, 0.74 mmol) in 1,4-dioxane (10 mL) and water (4 mL) was added5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.19 g, 0.93mmol), potassium phosphate (0.55 g, 2.60 mmol), tricyclohexylphosphine(0.021 g, 0.074 mmol), and palladium(II)acetate (0.008 g, 0.037 mmol).The reaction mixture was heated to 125° C. in a microwave reactor. After15 min, the reaction mixture was diluted with water. The mixture wasextracted with chloroform (×3), and the combined organic phases weredried over magnesium sulfate, filtered, and concentrated to provide 0.45g of a light green solid. Chromatographic purification (Combi-Flash, 12g SiO₂ gold column, 1-5% methanol/dichloromethane elute) afforded 0.14 g(40%) of the product as an off-white solid: ¹H NMR (400 MHz, DMSO-d₆) δ9.17-9.14 (m, 3H), 8.50 (s, 1H), 8.20 (d, J=2.5, 1H), 8.12 (d, J=1.7,1H), 7.77-7.70 (m, 2H), 7.65 (dd, J=8.4, 1.7 Hz, 1H), 7.12 (d, J=2.0 Hz,1H), 7.02 (d, J=8.4 Hz, 1H), 6.87-6.80 (m, 2H), 5.45 (s, 2H), 4.97 (s,2H), 3.84 (s, 3H), 3.74 (s, 3H) ppm; (M+1)=454.

Example 3-5: Synthesis of3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridinewas prepared from5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazoleand tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylateaccording to the procedure described in Example 3-4-6 for the synthesisof Example 3-4. The final product was obtained after removal of thecarbamate protecting under acidic conditions: ¹H NMR (500 MHz, CDCl₃) δ8.20 (d, J=2.0 Hz, 1H), 7.93 (s, 1H), 7.92 (s, 1H), 7.82 (s, 1H), 7.72(s, 1H), 7.68 (dd, J=8.5, 2.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.29 (d,J=8.0 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.5 Hz, 1H), 6.74 (d,J=8.5 Hz, 2H), 5.29 (s, 2H), 5.04 (s, 2H), 4.29-4.25 (m, 1H), 3.95 (s,3H), 3.79 (s, 3H), 3.29-3.27 (m, 2H), 2.83-2.78 (m, 2H), 2.23-2.21 (m,2H), 1.99-1.85 (m, 2H) ppm; (M+1)=525.

Example 3-6: Synthesis of1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-1H-benzo[d]imidazole

To a suspension of5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole(0.32 g, 0.63 mmol) in dimethyl sulfoxide (4 mL) and water (1 mL) wasadded 3-ethynylpiperidine hydrochloride (0.11 g, 0.75 mmol), sodiumazide (0.051 g, 0.79 mmol), L-ascorbic acid sodium salt (0.025 g, 0.13mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.023 mg, 0.158mmol), potassium carbonate (0.13 g, 0.95 mmol), and copper(I) iodide(0.024 g, 0.13 mmol). The resulting blue mixture was allowed to stir atroom temperature. After 16 h, the yellow mixture was diluted with 5Nammonium hydroxide solution and extracted with chloroform (2×30 mL). Thecombined organic phases were dried over magnesium sulfate, filtered, andconcentrated to provide 0.53 g of a yellow oil. Chromatographicpurification (Combi-Flash, 24 g SiO₂ gold column, 1-10% 2M ammonia inmethanol/dichloromethane elute) afforded 0.15 g (45%) of the product asa white foamy solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.61-8.53 (m, 2H), 8.20(d, J=2.4 Hz, 1H), 8.11 (d, J=1.9 Hz, 1H), 7.79-7.71 (m, 3H), 7.12 (d,J=1.9 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H), 6.89-6.80 (m, 2H), 5.46 (s, 2H),4.97 (s, 2H), 3.84 (s, 3H), 3.73 (s, 3H), 3.25-3.16 (m, 1H), 3.01-2.91(m, 1H), 2.90-2.80 (m, 1H), 2.68-2.51 (m, 2H), 2.12-2.03 (m, 1H),1.72-1.44 (m, 3H) ppm; (M+1)=526.

Example 3-7: Synthesis of2-(1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-5-(piperidin-4-yl)-1,3,4-oxadiazoleExample 3-7-1: Preparation of1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole-5-carbonitrile

To a stirred solution of5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole(1.00 g, 1.99 mmol) in N,N-dimethylformamide (20 mL) was added zinc(II)cyanide (0.64 g, 3.52 mmol), tetrakis(triphenylphosphine)palladium(O)(0.46 g, 0.40 mmol) and potassium carbonate (0.63 g, 4.54 mmol). Themixture was heated to 150° C. After 4 h, the mixture was allowed to coolto room temperature and was concentrated. The residue was purified bysilica gel chromatography (2% methanol/dichloromethane elute) to give0.70 g (87%) of1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole-5-carbonitrileas a yellow solid.

Example 3-7-2: Preparation of1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole-5-carboxylicacid

To a solution of1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole-5-carbonitrile(0.70 g, 1.75 mmol) in 1,4-dioxane (10 mL) was added 50% sodiumhydroxide solution (20 mL). The resulting mixture was heated to refluxand stirred. After 48 h, the reaction mixture was allowed to cool toroom temperature and was extracted with 10% methanol in dichloromethane.The extracts were washed with brine, dried and concentrated. The residuewas purified by Prep-HPLC to afford 0.50 g (68%) of1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole-5-carboxylicacid as a light yellow solid.

Example 3-7-3: Preparation of tert-butyl4-(2-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole-5-carbonyl)hydrazinecarbonyl)piperidine-1-carboxylate

To a solution of1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole-5-carboxylicacid (0.30 g, 0.72 mmol) in dichloromethane was added tert-butyl4-(hydrazinecarbonyl)piperidine-1-carboxylate (0.24 g, 0.98 mmol),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (0.34 g, 0.89 mmol), diisopropylamine (0.19g, 1.47 mmol). The resulting mixture was allowed to stir at roomtemperature. After 16 h, the mixture was concentracted and the residuewas purified by silica gel chromatography (2% methanol/dichloromethaneelute) to afford 0.30 g (65%) tert-butyl4-(2-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole-5-carbonyl)hydrazinecarbonyl)piperidine-1-carboxylateas a yellow solid.

Example 3-7-4: Preparation of tert-butyl4-(5-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate

To a stirred mixture of tert-butyl4-(2-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole-5-carbonyl)hydrazinecarbonyl)piperidine-1-carboxylate(0.18 g, 0.28 mmol) in 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide (T₃P) (2.70 g, 8.49 mmol) was added triethylamine (0.42g, 4.20 mmol). The resulting mixture was heated 120° C. and stirred.After 16 h, the mixture was extracted with dichloromethane. The extractswere washed with brine, dried and concentrated. The residue was purifiedby silica gel chromatography (1% methanol/dichloromethane elute) toafford 0.14 g (70%) of tert-butyl4-(5-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylateas a yellow solid.

Example 3-7-5: Preparation of2-(1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-5-(piperidin-4-yl)-1,3,4-oxadiazol

To a −20° C. solution of tert-butyl4-(5-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate(0.090 mg, 0.14 mmol) in dichloromethane (10 mL) was addedtrifluoroacetic acid (1.0 mL). The resulting mixture was stirred at −20°C. After 1 h, the mixture was concentrated. The residue was purified byPrep-HPLC to afford 0.010 g (14%) of the product as a yellow solid: ¹HNMR (500 MHz, CDCl₃) δ 8.43 (s, 1H), 8.19 (d, J=1.0 Hz, 1H), 8.02-8.01(m, 2H), 7.67 (dd, J=8.5, 2.0 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 6.89 (d,J=8.5 Hz, 1H), 6.76-6.72 (m, 3H), 5.32 (s, 2H), 5.03 (s, 2H), 3.93 (s,3H), 3.78 (s, 3H), 3.31-3.29 (m, 2H), 3.23-3.21 (m, 1H), 2.92-2.88 (m,2H), 2.23-2.21 (m, 2H), 2.02-1.98 (m, 2H) ppm; (M+1)=527.

Example 3-8: Synthesis of1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(piperidin-4-yl)-1H-benzo[d]imidazoleExample 3-8-1: Preparation of tert-butyl4-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate

To a stirred solution of5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole(0.801 g, 1.60 mmol) in 1,4-dioxane (10 mL) and 2 M sodium carbonatesolution (3.2 mL) was added 4-(4, 4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-5, 6-dihydropyridine-1(2H)-carboxylate (0.65 mg,2.10 mmol). The mixture was treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.12 mg,0.16 mmol) and heated to 100° C. After 16 h, the reaction mixture wasallowed to cool to room temperature and filtered. The filtrate wasdiluted with water (30 mL) and extracted with dichloromethane (3×50 mL).The combined organic layers were washed with brine (30 mL×2), dried oversodium sulfate, and concentrated. The residue was purified by silica gelchromatography (5% methanol/dichloromethane elute) to afford 0.79 mg(89%) of tert-butyl4-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylateas a light yellow solid.

Example 3-8-2: Preparation of tert-butyl4-(1-(4-hydroxy-3-methoxybenzyl)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate

To a stirred solution of tert-butyl4-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.56 g, 1.00 mmol) in methanol (15 mL) was added ammonium formate (0.63g, 10 mmol) and palladium on carbon (0.30 g). The reaction mixture washeated to 60° C. under H₂. After 16 h, the reaction mixture was allowedto cool to room temperature and was filtered through Celite. Thefiltrate was concentrated. The residue was purified by silica gelchromatography (5% methanol/dichloromethane elute) to afford 0.42 g(96%) of tert-butyl4-(1-(4-hydroxy-3-methoxybenzyl)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylateas a light yellow solid.

Example 3-8-3: Preparation of tert-butyl4-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate

To a stirred solution of tert-butyl4-(1-(4-hydroxy-3-methoxybenzyl)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate(0.51 g, 1.16 mmol) in N,N-dimethylformamide (5 mL) was added potassiumcarbonate (0.32 g, 2.32 mmol). The mixture was treated with a solutionof 5-(chloromethyl)-2-methoxypyridine (219 mg, 1.39 mmol) inN,N-dimethylformamide (2 mL) added dropwise. The mixture was stirred atroom temperature. After 16 h, the mixture was diluted with saturatedammonium chloride solution (20 mL) and extracted with ethyl acetate(3×30 mL). The combined organic layers were washed with brine (3×10 mL),dried over sodium sulfate, filtered and concentrated to afford 0.53 g(82%) of tert-butyl4-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylateas a light yellow solid.

Example 3-8-4: Preparation of1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(piperidin-4-yl)-1H-benzo[d]imidazole

To a stirred and cooled (5° C.) solution of tert-butyl4-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate(0.28 g, 0.51 mmol) in dichloromethane (1 mL) was added trifluoroaceticacid (1 mL). The resulting mixture was allowed to warm room temperatureand stir. After 2 h, the mixture was treated with 1 N sodium hydroxidesolution to achieve a pH 10 and was extracted with dichloromethane (3×10mL). The combined organic layers were washed with brine (3×10 mL), driedover sodium sulfate, concentrated. The residue was purified by prep-HPLCto afford 0.018 g (8%) of the product as a white solid: ¹H NMR (500 MHz,MeOD-d₄) δ 8.25 (s, 1H), 8.16 (d, J=2.5 Hz, 1H), 7.76 (dd, J=8.5, 2.5Hz, 1H), 7.55 (s, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.20 (dd, J=8.5, 1.0 Hz,1H), 7.00-6.97 (m, 2H), 6.82-6.79 (m, 2H), 5.41 (s, 2H), 5.01 (s, 2H),3.91 (s, 3H), 3.79 (s, 3H), 3.24-3.21 (m, 2H), 2.86-2.81 (m, 3H),1.93-1.90 (m, 2H), 1.78-1.75 (m, 2H) ppm; (M+1)=459.

Example 3-9: Synthesis of4-(1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)morpholine

To a suspension of5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole(0.32 g, 0.64 mmol) in dimethyl sulfoxide (4 mL) was added morpholine(0.067 g, 0.77 mmol), copper(I) iodide (0.015 g, 0.076 mmol), potassiumcarbonate (0.22 g, 1.54 mmol), and L-proline (0.018 g, 0.15 mmol). Thelight yellow reaction mixture was heated to 120° C. After 16 h, thereaction mixture was allowed to cool to room temperature and was dilutedwith 3 N ammonium hydroxide solution (20 mL). The mixture was extractedwith dichloromethane (×3). The combined organic phases were washed withwater (×2), brine, dried over magnesium sulfate, filtered, andconcentrated. Chromatographic purification (CombiFlash, 40 g SiO2column, 1-5% methanol/dichloromethane elute) afforded 0.076 g (26%) ofthe product as an off-white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d,J=1.9 Hz, 1H), 7.85 (s, 1H), 7.66 (dd, J=8.5, 2.5 Hz, 1H), 7.35-7.13 (m,2H), 6.98 (dd, J=8.8, 2.2 Hz, 1H), 6.90-6.82 (m, 1H), 6.78-6.67 (m, 3H),5.23 (s, 2H), 5.02 (s, 2H), 3.93 (s, 3H), 3.95-3.85 (m, 4H), 3.76 (s,3H), 3.18-3.12 (m, 4H) ppm; (M+1)=461.

Example 3-10: Synthesis of2-(1-(1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)propan-2-amineExample 3-10-1: Preparation of 2-(piperidin-4-yl)propan-2-amineDihydrochloride

A stirred suspension of cesium(III) chloride (5.27 g, 21.40 mmol) intetrahydrofuran (50 mL) was heated to 60° C. After 2 h, the mixture wasallowed to cool to room temperature and was treated with tert-butyl4-cyanopiperidine-1-carboxylate (2.25 g, 10.70 mmol). The mixture wascooled to −20° C. while a 1.5 M solution of methyllithium lithiumbromide complex (21.4 mL, 32.10 mmol) was added. After 1 h at −20° C.,the mixture was quenched with saturated ammonium chloride solution anddiluted with ethyl acetate. The biphasic mixture was filtered to removethe undissolved solid material, and the layers of the filtrate wereseparated. The organic phase was washed with brine, dried over magnesiumsulfate, filtered, and concentrated. The residue was treated with Dowex50-WX8-200 acidic resin in methanol (1.1 eq/mL, 20 mL added). After 2 hat room temperature, the mixture was filtered. The filtercake was washedwith methanol followed by ammonia in methanol (3 M to 6 M). The filtratewas concentrated to provide a waxy solid (containing both the freediamine and the carbamate-protected monoamine). This crude mixture wasdissolved in methanol and was treated with hydrogen chloride (2.0 M indiethyl ether). The mixture was allowed to stir at room temperature.After 20 h, the mixture was concentrated. The residue was suspended intoluene and reconcentrated to afford 0.96 g (42%) of2-(piperidin-4-yl)propan-2-amine dihydrochloride as a white solid.

Example 3-10-2: Preparation of2-(1-(1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)propan-2-amine

To a stirred suspension of5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole(0.15 g, 0.30 mmol) in dimethyl sulfoxide (5 mL) was added2-(piperidin-4-yl)propan-2-amine dihydrochloride (0.19 g, 0.90 mmol),copper(I) iodide (0.005 g, 0.030 mmol), potassium carbonate (0.25 g,1.80 mmol), and L-proline (0.007 g, 0.057 mmol). The light yellowreaction mixture was heated to 100° C. After 24 h, an additional portionof L-proline (0.007 g, 0.057 mmol) was added and heating continued.After an additional 5 h, the reaction mixture was allowed to cool toroom temperature and was diluted with ammonium hydroxide solution andethyl acetate. The organic phase was separated and washed with saturatedsodium bicarbonate solution (×2), brine, dried over magnesium sulfate,filtered, and concentrated. Chromatographic purification (Biotage, 10 gSiO2 column, 10% methanol/dichloromethane to 3 M ammonia inmethanol/dichloromethane elute) provided an oil. The oil was dissolvedin aqueous acetonitrile and lyophilized to afford 0.070 g (45%) of theproduct as tan solid: ¹H NMR (400 MHz, CDCl₃) 8.20 (s, 1H), 7.85 (s,1H), 7.67 (d, J=8.0 Hz, 1H), 7.35 (s, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.03(d, J=8.0 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.77-6.72 (m, 2H), 6.71 (s,1H), 5.23 (s, 2H), 5.03 (s, 2H), 3.94 (s, 3H), 3.77 (s, 3H), 3.72-3.68(m, 2H), 2.67 (t, J=12.0 Hz, 2H), 1.89 (dd, J=12.0, 4.0 Hz, 2H),1.53-1.50 (m, 2H), 1.35-1.25 (m, 1H), 1.15 (s, 6H) ppm; (M+1)=516.

Example 3-11: Synthesis of1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(2,7-diazaspiro[3.5]nonan-2-yl)-1H-benzo[d]imidazoleExample 3-11-1: Preparation of tert-butyl2-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

To a stirred suspension of5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole(0.61 g, 1.22 mmol) in dimethyl sulfoxide (4 mL) was added tert-butyl2,7-diazaspiro[3.5]nonane-7-carboxylate (0.30 g, 1.34 mmol), copper(I)iodide (0.028 g, 0.15 mmol), potassium carbonate (0.41 g, 2.94 mmol),and L-proline (0.034 g, 0.29 mmol). The light yellow reaction mixturewas heated to 120° C. After 16 h, the reaction mixture was allowed tocool to room temperature and was diluted with 3 N ammonium hydroxidesolution (20 mL). The mixture was extracted with dichloromethane,resulting in a thick emulsion. The emulsion was filtered through Celiteto remove any insoluble material. The organic phase was washed withwater, brine, dried over magnesium sulfate, filtered, and concentrated.Chromatographic purification (CombiFlash, 40 g SiO2 column, 1-5%methanol/dichloromethane elute) afforded 0.53 g (72%) of tert-butyl2-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate.

Example 3-11-2: Preparation of1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(2,7-diazaspiro[3.5]nonan-2-yl)-1H-benzo[d]imidazole

To a stirred solution of tert-butyl2-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate(0.53 g, 0.88 mmol) in dichloromethane (10 mL) was added trifluoroaceticacid (5.0 mL. 64.90 mmol). The reaction mixture was allowed to stir atroom temperature. After 1 h, the mixture was concentrated, and theresidue partitioned between 3 M ammonium hydroxide solution anddichloromethane. The phases were separated, and the aqueous phase wasextracted with dichloromethane. The combined organic phases were washedwith brine, dried over magnesium sulfate, filtered, and concentrated.Chromatographic purification (Combi-Flash, 40 g SiO₂ gold column, 1-15%methanol/dichloromethane elute) afforded 0.28 g (64%) of the product asa solid: ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J=2.1 Hz, 1H), 7.80 (s, 1H),7.65 (dd, J=8.5, 2.4 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.88-6.79 (m, 2H),6.78-6.65 (m, 3H), 6.47 (dd, J=8.6, 2.1 Hz, 1H), 5.18 (s, 2H), 5.00 (s,2H), 3.92 (s, 3H), 3.75 (s, 3H), 3.61 (s, 4H), 2.86-2.78 (m, 4H), 2.54(b, 1H), 1.82-1.74 (m, 4H) ppm; (M+1)=500.

Example 3-12: Synthesis of1-(1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)piperidin-4-amineExample 3-12-1: Preparation of tert-butyl(1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)carbamate

To a suspension of5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole(0.48 g, 0.96 mmol) in dimethyl sulfoxide (4 mL) was added tert-butylpiperidin-4-ylcarbamate (0.22 g, 1.05 mmol), copper(I) iodide (0.022 g,0.11 mmol), potassium carbonate (0.32 g, 2.32 mmol), and L-proline(0.026 g, 0.23 mmol). The light yellow reaction mixture was heated to120° C. After 16 h, additional portions tert-butylpiperidin-4-ylcarbamate (0.048 g, 0.47 mmol), copper(I) iodide (0.018 g,0.095 mmol), and L-proline (0.022 g, 0.19 mmol) were added. Heating wascontinued for an additional 4 h. After a total of 20 h, the reactionmixture was allowed to cool to room temperature and was diluted with 3 Nammonium hydroxide solution (25 mL). The mixture was extracted withdichloromethane (×3). The combined organic phases were washed with water(×2), brine, dried over magnesium sulfate, filtered, and concentrated.Chromatographic purification (CombiFlash, 40 g SiO2 column, 1-10%methanol/dichloromethane elute) afforded 0.33 g (60%) of tert-butyl(1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)carbamateas an impure solid.

Example 3-12-2: Preparation of1-(1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)piperidin-4-amine

To a stirred solution of tert-butyl(1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)carbamate(0.33 g, 0.58 mmol) in dichloromethane (10 mL) was added trifluoroaceticacid (5.0 mL. 64.90 mmol). The reaction mixture was allowed to stir atroom temperature. After 2 h, the mixture was concentrated, and theresidue partitioned between 3 M ammonium hydroxide solution anddichloromethane. The phases were separated, and the aqueous phase wasextracted with dichloromethane. The combined organic phases were washedwith brine, dried over magnesium sulfate, filtered, and concentrated.Chromatographic purification (Combi-Flash, 40 g SiO₂ gold column, 1-15%methanol/dichloromethane elute) afforded 0.19 g (62%) of the product asa solid: ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J=2.0 Hz, 1H), 7.83 (s, 1H),7.65 (dd, J=8.5, 2.4 Hz, 1H), 7.36-7.26 (m, 1H), 7.15 (d, J=8.8 Hz, 1H),7.01 (dd, J=8.8, 2.2 Hz, 1H), 6.89-6.82 (m, 1H), 6.78-6.67 (m, 3H), 5.21(s, 2H), 5.01 (s, 2H), 3.93 (s, 3H), 3.76 (s, 3H), 3.60-3.52 (m, 2H),2.85-2.72 (m, 3H), 1.98-1.90 (m, 2H), 1.80 (b, 2H), 1.62-1.50 (m, 2H)ppm; (M+1)=474.

Example 3-13: Synthesis of1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazole

To a stirred suspension of5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole(0.25 g, 0.50 mmol) in dimethyl sulfoxide (5 mL) was added1-methylpiperazine (0.28 g, 1.50 mmol), copper(I) iodide (0.029 g, 0.15mmol), sodium carbonate (0.32 g, 2.60 mmol), and L-proline (0.035 g,0.30 mmol). The mixture was heated to 90° C. in a microwave reactor.After 1 h, the reaction mixture was allowed to cool to room temperatureand was filtered through Celite. The filtrate was concentrated, and theresidue purified via prep-HPLC to afford 0.045 g (19%) of the product asa white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.20 (d, J=2.5 Hz, 1H), 7.87(s, 1H), 7.68 (dd, J=8.5, 2.0 Hz, 1H), 7.36 (d, J=1.0 Hz, 1H), 7.18 (d,J=9.0 Hz, 1H), 7.02 (dd, J=9.0, 2.0 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H),6.77 (d, J=8.5 Hz, 1H), 6.73-6.72 (m, 2H), 5.25 (s, 2H), 5.04 (s, 2H),3.95 (s, 3H), 3.78 (s, 3H), 3.24-3.18 (m, 4H), 2.67-2.62 (m, 4H), 2.39(s, 3H) ppm; (M+1)=474.

Example 3-14: Synthesis of1-(2-Amino-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-4-methylpiperazin-2-oneExample 3-14-1: Preparation of5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-2-amine

To a stirred suspension of4-iodo-N-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)benzene-1,2-diamine(3.82 g, 7.77 mmol) in dichloromethane (40 mL) and methanol (20 mL) wasadded cyanogen bromide solution (5.0 M in acetonitrile, 7.8 mL, 38.87mmol). The resulting brown reaction mixture was allowed to stir at roomtemperature. After 18 h, the mixture was treated with 1N sodiumhydroxide solution (50 mL) and allowed to stir. After 30 min, the phaseswere separated, and the aqueous phase was extracted with chloroform. Thecombined organic phases were dried over magnesium sulfate, filtered, andconcentrated to provide 5.26 g of a brown semi solid. Chromatographicpurification (Combi-Flash, 80 g SiO2 column, 5-10%methanol/dichloromethane elute) afforded 2.78 g (69%) of5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-2-amineas a brown solid.

Example 3-14-2: Preparation of1-(2-Amino-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-4-methylpiperazin-2-one

To a stirred suspension of5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-2-amine(0.25 g, 0.48 mmol) in 1,4-dioxane (8 mL) was added4-methylpiperazin-2-one (0.11 g, 0.96 mmol), CuI (0.036 mg, 0.19 mmol),trans-N,N-dimethylcyclohexane-1,2-diamine (0.044 g, 0.38 mmol), andtribasic potassium phosphate (0.32 g, 1.52 mmol). The mixture was heatedto 145° C. in a microwave reactor. After 3 h, the mixture was allowed tocool to room temperature and was filtrated through Celite. The filtratewas concentrated, and the residue was purified by silica gelchromatography (2-5% methanol/dichloromethane elute) followed byprep-HPLC to afford 0.030 g (12%) of the product as a white solid: ¹HNMR (500 MHz, CDCl₃) δ 8.17 (s, 1H), 7.66 (dd, J=8.0, 2.0 Hz, 1H), 7.25(s, 1H), 7.01 (d, J=8.0 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.79 (d, J=8.0Hz, 1H), 6.76-6.74 (m, 2H), 6.64 (d, J=7.5 Hz, 1H), 4.99 (s, 2H), 4.89(br s, 2H), 4.81 (s, 2H), 3.94 (s, 3H), 3.79 (s, 3H), 3.72 (t, J=5.0 Hz,2H), 3.30 (s, 2H), 2.82 (t, J=5.0 Hz, 2H), 2.44 (s, 3H) ppm; (M+1)=503.

Example 3-15: Synthesis of3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amineExample 3-15-1: Preparation of5-bromo-N-(3-methoxy-4-(4-methoxybenzyloxy)benzyl)-3-nitropyridin-2-amine

To a stirred solution of3-methoxy-4-(4-methoxybenzyloxy)phenyl)methanamine (2.00 g, 7.32 mmol)and 5-bromo-2-chloro-3-nitropyridine (1.66 g, 6.97 mmol) in acetonitrile(50 mL) was added N,N-diisopropylethylamine (1.13 g, 8.71 mmol). Theresulting mixture was heated to reflux and allowed to stir. After 64 h,the reaction mixture was allowed to cool to room temperature and wasdiluted with water. The mixture was extracted twice withdichloromethane. The combined organic phases were dried over magnesiumsulfate, filtered, and concentrated to provide 3.34 g (>100%) of5-bromo-N-(3-methoxy-4-(4-methoxybenzyloxy)benzyl)-3-nitropyridin-2-amineas a yellow-brown solid.

Example 3-15-2: Preparation of5-bromo-N²-(3-methoxy-4-(4-methoxybenzyloxy)benzyl)pyridine-2,3-diamine

To a stirred solution of5-bromo-N-(3-methoxy-4-(4-methoxybenzyloxy)benzyl)-3-nitropyridin-2-aminein tetrahydrofuran (40 mL), ethanol (40 mL), and water (40 mL) was addedsodium hydrosulfite (6.09 g, 34.99 mmol). The resulting mixture washeated to reflux and allowed to stir. After 4 h, the reaction mixturewas allowed to cool to room temperature and was diluted with water. Theyellow mixture was extracted three times with dichloromethane. Thecombined organic phases were washed with brine, dried (magnesiumsulfate), filtered, and concentrated to provide 3.10 g of a yellow-brownsolid. Chromatographic purification (Combi-Flash 40 g SiO₂ gold column,1-2.5% methanol/dichloromethane) afforded 1.28 g (51%) of5-bromo-N²-(3-methoxy-4-(4-methoxybenzyloxy)benzyl)pyridine-2,3-diamineas a yellow solid.

Example 3-15-3: Preparation of6-bromo-3-(3-methoxy-4-(4-methoxybenzyloxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amine

To a stirred solution of5-bromo-N²-(3-methoxy-4-(4-methoxybenzyloxy)benzyl)pyridine-2,3-diamine(0.850 g, 1.91 mmol) in dichloromethane (30 mL) and methanol (30 mL) wasadded cyanogen bromide (5.0 M in acetontitrile, 573 μL, 2.87 mmol). Theresulting solution was allowed to stir at room temperature. After 24 h,a second aliquot of cyanogen bromide solution was added (600 μL) andstirring continued. After 48 h, a third aliquot of cyanogen bromidesolution (600 μL) was added and stirring continued. After a total of 72h, the reaction mixture was concentrated, and the residue was dissolvedin dichloromethane. The solution was washed with 1N sodium hydroxidesolution, dried over magnesium sulfate, filtered, and concentrated toprovide 1.17 g of a brown solid. Chromatographic purification(Combi-Flash, 40 g SiO₂ gold column, 1-10% 2M ammonia inmethanol/dichloromethane) afforded 0.28 g (32%) of6-bromo-3-(3-methoxy-4-(4-methoxybenzyloxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amineas a brown solid.

Example 3-15-4: Preparation of3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

To a stirred solution of6-bromo-3-(3-methoxy-4-(4-methoxybenzyloxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amine(0.25 g, 0.53 mmol) in 1,4-dioxane (10 mL) and water (4 mL) was added1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.14 g, 0.66 mmol), potassium phosphate tribasic (0.39 g, 1.84 mmol),tricyclohexylphosphine (0.015 g, 0.052 mmol), palladium(II) acetate(0.005 g, 0.026 mmol). The reaction mixture heated to 125° C. in amicrowave reactor. After 15 min, the reaction mixture was allowed tocool to room temperature and was diluted with water. The mixture wasextracted twice with ethyl acetate. The combined organic phases werewashed with brine, dried over magnesium sulfate, filtered, andconcentrated to provide 0.36 g of a greenish brown solid.Chromatographic purification (Combi-Flash, 12 g SiO₂ gold column, 1-10%2M ammonia in methanol/dichloromethane) afforded 0.10 g (41%) of theproduct as a light green solid: ¹H NMR (400 MHz, DMSO-d6) δ 8.12-8.08(m, 2H), 7.83 (d, J=0.6 Hz, 1H), 7.58 (d, J=1.9 Hz, 1H), 7.32 (d, J=8.7Hz, 2H), 7.08 (d, J=1.9 Hz, 1H), 6.96-6.85 (m, 5H), 6.72 (dd, J=8.3, 1.9Hz, 1H), 5.18 (s, 2H), 4.92 (s, 2H), 3.85 (s, 3H), 3.74 (s, 3H), 3.70(s, 3H) ppm, (M+1)=471.

Example 3-16: Synthesis of(5-(2-Amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)dimethylphosphineoxide Example 3-16-1: Preparation of5-iodo-N-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3-nitropyridin-2-amine

To a stirred solution of3-methoxy-4-(4-methoxybenzyloxy)phenyl)methanamine (3.80 g, 13.92 mmol)and 2-chloro-5-iodo-3-nitropyridine (3.77 g, 13.25 mmol) in acetonitrile(50 mL) was added potassium carbonate (2.29 g, 16.57 mmol). Theresulting bright yellow mixture was heated to reflux and allowed tostir. After 16 h, the brown reaction mixture was allowed to cool to roomtemperature and was diluted with water. The mixture was extracted withchloroform (×3). The combined organic phases were dried over magnesiumsulfate, filtered, and concentrated to provide 6.88 g (>100%) of5-iodo-N-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3-nitropyridin-2-amineas a yellow-brown solid.

Example 3-16-2: Preparation of5-iodo-N²-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyridine-2,3-diamine

To a stirred suspension of5-iodo-N-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3-nitropyridin-2-amine(6.72 g, 13.25 mmol) in tetrahydrofuran (75 mL), methanol (25 mL), andwater (25 ml) was added ammonium chloride (5.68 g, 106.0 mmol) andiron(II) sulfate heptahydrate (11.05 g, 39.76 mmol). The yellow mixturewas treated with zinc (2.60 g, 39.76 mmol), and the resulting darkmixture was heated to reflux. After 3 h, the reaction mixture wasallowed to cool to room temperature and was filtered through Celite withthe aid of methanol. The filtrate was concentrated, and the residue wasdissolved in chloroform. The solution was washed with water, filteredthrough Celite, dried over magnesium sulfate, filtered, and concentratedto provide 6.67 g (>100%) of5-iodo-N²-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyridine-2,3-diamineas a brown solid.

Example 3-16-3: Preparation of6-iodo-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amine

To a stirred suspension of5-iodo-N²-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyridine-2,3-diamine(6.33 g, 13.25 mmol) in dichloromethane (100 mL) and methanol (50 mL)was added cyanogen bromide solution (5.0M in acetonitrile, 13.3 mL,66.27 mmol). The resulting dark brown reaction mixture was allowed tostir at room temperature. After 68 h, the now black reaction mixture wastreated with 1N sodium hydroxide solution (75 mL) and stirred at roomtemperature. After 30 min, the mixture was diluted with water, and thephases were separated. The organic phase was dried over magnesiumsulfate, filtered, and concentrated to provide 6.43 g of a brown oil.Chromatographic purification (Combi-Flash, 120 g SiO2 column, 1-5% 2Mammonia in methanol/dichloromethane elute) provided 2.40 g of a blackoil. A second chromatographic purification (Combi-Flash, 80 g SiO2column, 1-5% 2M ammonia in methanol/dichloromethane elute) afforded 0.98g (14%) of6-iodo-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amineas a gray solid.

Example 3-16-4: Preparation of6-(6-chloropyridin-3-yl)-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amine

To a stirred suspension of6-iodo-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amine(0.34 g, 0.66 mol) in 1,4-dioxane (10 mL) and water (4 mL) was added(6-chloropyridin-3-yl)boronic acid (0.12 g, 0.76 mmol), potassiumphosphate tribasic (0.49 g, 2.33 mmol), tricyclohexylphosphine (0.037 g,0.13 mmol), and palladium(II) acetate (0.015 g, 0.066 mmol). Thereaction mixture was heated to 125° C. in a microwave reactor. After 30min, the reaction mixture was diluted with water. The mixture wasextracted with chloroform (×3). The combined organic phases were driedover magnesium sulfate, filtered, and concentrated to provide 0.44 g ofa brown solid. Chromatographic purification (Combi-Flash, 24 g SiO₂ goldcolumn, 5-10% methanol/dichloromethane elute) afforded 0.20 g (60%) of6-(6-chloropyridin-3-yl)-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amineas a tan solid.

Example 3-16-5: Preparation of(5-(2-Amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)dimethylphosphineoxide

To a stirred suspension of6-(6-chloropyridin-3-yl)-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amine(0.17 g, 0.34 mmol) in 1,4-dioxane (12 mL) was added dimethylphosphineoxide (0.053 g, 0.69 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.079 g, 0.14 mmol),palladium(II) acetate (0.015 g, 0.069 mmol), and cesium carbonate (0.22g, 0.69 mmol). The reaction mixture was heated to 150° C. in a microwavereactor. After 1 h, the reaction mixture was allowed to cool to roomtemperature. The mixture was diluted with water and extracted withchloroform (×2). The combined organic phases were dried over magnesiumsulfate, filtered, and concentrated to provide 0.27 g of a yellow solid.Chromatographic purification (Combi-Flash, 12 g SiO2 column, 5-10% 2Mammonia in methanol/dichloromethane elute) afforded 0.078 g (42%) of theproduct as a tan solid: ¹H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J=1.8 Hz,1H), 8.32-8.21 (m, 2H), 7.99 (dd, J=7.9, 5.1 Hz, 1H), 7.82 (d, J=1.8 Hz,1H), 7.32 (d, J=8.6 Hz, 2H), 7.11 (d, J=1.7 Hz, 1H), 7.05 (s, 2H),6.98-6.87 (m, 3H), 6.72 (dd, J=8.2, 1.7 Hz, 1H), 5.24 (s, 2H), 4.93 (s,2H), 3.74 (s, 3H), 3.72 (s, 3H), 1.69 (d, J=13.5 Hz, 6H) ppm; (M+1)=544.

Example 3-17: Synthesis of3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridineExample 3-17-1: Preparation of5-iodo-N-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3-nitropyridin-2-amine

To a stirred solution of(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine (9.11 g,33.21 mmol) in acetonitrile (150 mL) was added2-chloro-5-iodo-3-nitropyridine (9.90 g, 34.81 mmol) andN,N-diisopropylethylamine (6.44 g, 49.81 mmol). The yellow solution washeated to reflux and stirred. After 3 h, the red-brown mixture wascooled to 0° C. resulting in the formation of a precipitate. Theprecipitate was isolated by filtration and washed with acetonitrile (50mL) and water (200 mL). The moist solids were dissolved indichloromethane, and a small amount of water separated and was removed.The organic phase was dried over magnesium sulfate, filtered, andconcentrated to provide 14.67 g (85%) of5-iodo-N-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3-nitropyridin-2-amineas a yellow-brown solid.

Example 3-17-2: Preparation of5-iodo-N²-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)pyridine-2,3-diamine

To a stirred suspension of5-iodo-N-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3-nitropyridin-2-amine(14.67 g, 28.09 mmol) in acetic acid (130 mL) was added iron powder(10.98 g, 196.6 mmol). The bright yellow mixture was warmed to ˜85° C.After 15 min of heating, the reaction mixture became a gray-brownsuspension and was allowed to cool to room temperature. The mixture wasdiluted with ethyl acetate (400 mL), and the thick mixture was filteredthrough Celite with the aid of additional ethyl acetate (100 mL). Thefiltrate was washed with water (2×150 mL) and 5N ammonium hydroxidesolution (4×125 mL). The organic phase was dried over magnesium sulfate,filtered, and concentrated to provide 11.67 g (84%) of5-iodo-N²-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)pyridine-2,3-diamineas a tan solid.

Example 3-17-3: Preparation of6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine

To a stirred suspension of5-iodo-N²-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)pyridine-2,3-diamine(11.67 g, 23.70 mmol) in ethanol (175 mL) was added triethylorthoformate (8.90 g, 60.05 mmol) and p-toluenesulfonic acid monohydrate(0.23 g, 1.19 mmol). As the mixture was warmed to reflux, the solidsdissolved to provide a brown solution. After 30 min, the reactionmixture was cooled to 0° C., resulting in the formation of aprecipitate. The solids were isolated by filtration, washed with a smallamount of cold ethanol, and dried to provide 10.34 g (87%) of6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridineas an off-white solid.

Example 3-17-4: Preparation of3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine

To a stirred suspension of6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine(1.40 g, 2.79 mmol) in dimethylsulfoxide (15 mL) was added1-methylpiperazine (0.44 g, 4.40 mmol), copper(I) iodide (0.16 g, 0.84mmol), L-proline (0.19 g, 1.67 mmol), and potassium carbonate (0.96 g,6.97 mmol). The mixture was degassed under vacuum/backfilled with N2(×3), and then it was heated to 120° C. As the mixture warmed, it becamedark blue/black in color. After 19 h, the brown mixture was allowed tocool to room temperature and was diluted with 5N ammonium hydroxidesolution (100 mL). The mixture was extracted with dichloromethane (3×50mL). The combined organic phases were dried over magnesium sulfate,filtered, and concentrated to provide 1.78 g of a brown oil.Chromatographic purification (Combi-Flash, 40 g SiO2 gold column, 1-10%2M ammonia in methanol/dichloromethane elute) afforded 0.60 g (45%) ofthe product as a tan solid: ¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J=2.4 Hz,1H), 8.18 (d, J=2.4 Hz, 1H), 7.92 (s, 1H), 7.69-7.61 (m, 2H), 6.91-6.84(m, 2H), 6.80 (dd, J=8.2, 2.0 Hz, 1H), 6.74 (dd, J=8.5 Hz, 1H), 5.34 (s,2H), 5.02 (s, 2H), 3.93 (s, 3H), 3.80 (s, 3H), 3.25-3.18 (m, 4H),2.68-2.61 (m, 4H), 2.38 (s, 3H) ppm; (M+1)=475.

Example 3-18: Synthesis of Additional Compounds from6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine

The following compounds6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridineusing the procedure described in Example 3-17-4 by employing theappropriate amine coupling partner:

Example 3-18-1:2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)piperidin-4-yl)propan-2-amine

¹H NMR (400 MHz, CDCl₃): 8.20 (s, 1H), 8.11 (s, 1H), 7.85 (s, 1H),7.58-7.56 (m, 2H), 6.81 (d, J=8.0 Hz, 1H), 6.78 (s, 1H), 6.74 (dd,J=8.0, 4.0 Hz, 1H), 6.67 (d, J=8.0 Hz, 1H), 5.27 (s, 2H), 4.95 (s, 2H),3.85 (s, 3H), 3.72 (s, 3H), 3.62-3.57 (m, 2H), 2.65 (t, J=12.0 Hz, 2H),1.83 (dd, J=12.0, 4.0 Hz, 2H), 1.52-1.48 (m, 2H), 1.26-1.24 (m, 1H),1.06 (s, 6H) ppm; (M+1) 517.

Example 3-18-2:4-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)morpholine

¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, J=2.5 Hz, 1H), 8.18 (d, J=2.0 Hz,1H), 7.95 (s, 1H), 7.70-7.59 (m, 2H), 6.92-6.71 (m, 4H), 5.35 (s, 2H),5.02 (s, 2H), 3.95-3.88 (m, 7H), 3.80 (s, 3H), 3.21-3.13 (m, 4H) ppm;(M+1) 462.

Example 3-18-3:6-(4-Cyclopropylpiperazin-1-yl)-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (s, 1H), 8.24-8.18 (m, 2H), 7.73 (dd,J=8.4, 2.5 Hz, 1H), 7.58 (d, J=2.5 Hz, 1H), 7.10 (d, J=2.0 Hz, 1H), 6.99(d, J=8.4 Hz, 1H), 6.85-6.78 (m, 2H), 5.34 (s, 2H), 4.96 (s, 2H), 3.84(s, 3H), 3.72 (s, 3H), 3.13-3.05 (m, 4H), 2.75-2.67 (m, 4H), 1.70-1.63(m, 1H), 0.48-0.41 (m, 2H), 0.37-0.30 (m, 2H) ppm; (M+1) 501

Example 3-18-4:4-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1,4-diazabicyclo[3.2.2]nonane

¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J=2.6, 1H), 8.14 (d, J=2.6 Hz, 1H),7.89 (s, 1H), 7.66 (dd, J=8.5, 2.5 Hz, 1H), 7.49 (d, J=2.5 Hz, 1H),6.92-6.83 (m, 2H), 6.81 (d, J=8.2, 2.0 Hz, 1H), 6.74 (d, J=8.5 Hz, 1H),5.32 (s, 2H), 5.02 (s, 2H), 3.93 (s, 3H), 3.80 (s, 3H), 3.54-3.46 (m,2H), 3.24-2.99 (m, 7H), 2.21-2.09 (m, 2H), 1.81-1.69 (m, 2H) ppm; (M+1)501.

Example 3-18-5:3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(2,7-diazaspiro[3.5]nonan-2-yl)-3H-imidazo[4,5-b]pyridine

Synthesis is a two-step process including coupling followed by carbamatedeprotection as described for Example 3-11.

¹H NMR (400 MHz, CDCl₃) δ 8.21-8.16 (m, 1H), 7.93-7.88 (m, 1H),7.79-7.73 (m, 1H), 7.70-7.62 (m, 1H), 7.14-7.09 (m, 1H), 6.91-6.71 (m,4H), 5.32 (s, 2H), 5.02 (s, 2H), 3.93 (s, 3H), 3.80 (s, 3H), 3.72-3.67(m, 4H), 3.10 (b, 1H) 2.90 (s, 4H), 1.90-1.84 (m, 4H) ppm; (M+1) 501.

Example 3-18-6:1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)piperidin-4-amine

Synthesis is a two-step process including coupling followed by carbamatedeprotection as described for Example 3-12.

¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J=2.5 Hz, 1H), 8.18 (d, J=2.1 Hz,1H), 7.93 (s, 1H), 7.70-7.60 (m, 2H), 6.93-6.71 (m, 4H), 5.34 (s, 2H),5.01 (s, 2H), 3.92 (s, 3H), 3.80 (s, 3H), 3.59-3.51 (m, 2H), 2.88-2.77(m, 3H), 2.42 (b, 2H), 2.01-1.94 (m, 2H), 1.66-1.51 (m, 2H) ppm; (M+1)475.

Example 3-18-7:(S)-1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyrrolidine-2-carboxylicacid

¹H NMR (500 MHz, CD₃D) δ 8.31-8.19 (m, 1H), 8.17-8.13 (m, 1H), 7.87 (brs, 1H), 7.64 (dd, J=8.5, 2.5 Hz, 1H), 7.22-7.11 (m, 1H), 7.04 (s, 1H),6.95 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.79 (d, J=8.5 Hz, 1H),5.38 (s, 2H), 4.98 (s, 2H), 4.22-4.12 (m, 1H), 3.90 (s, 3H), 3.78 (s,3H), 3.68-3.58 (m, 1H), 3.42-3.39 (m, 1H), 2.37-2.08 (m, 4H) ppm; (M+1)490.

Example 3-19: Synthesis of3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridineExample 3-19-1: Preparation of tert-butyl4-(4-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

To a stirred suspension of6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine(0.20 g, 0.40 mmol) in N,N-dimethylformamide (8 mL) and water (2 mL) wasadded tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.15 g, 0.40 mmol), potassium carbonate (0.22 g, 1.59 mmol), andtetrakis(triphenylphosphino)palladium(O) (0.021 g, 0.018 mmol). Themixture was heated to 100° C. After 1 h, the reaction mixture wasallowed to cool to room temperature and was filtered through Celite. Thefiltrate was concentrated, and the residue purified via silica gelchromatography (5% methanol/dichloromethane elute) to provide 0.15 g(60%) of tert-butyl4-(4-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylateas a yellow solid.

Example 3-19-2: Preparation of3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

To a stirred solution of tert-butyl4-(4-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(0.15 g, 0.24 mmol) in dichloromethane (10 mL) was added trifluoroaceticacid (0.5 mL). The resulting mixture was stirred at room temperature.After 1 h, the reaction mixture was concentrated, and the residue wasdiluted with 1M potassium carbonate solution (20 mL) and extracted withdichloromethane (3×10 mL). The combined organic phases were washed withbrine (3×20 mL), dried over sodium sulfate, filtered, and concentrated.The residue was purified by Prep-HPLC to afford 0.065 g (52%) of theproduct as a white solid: ¹H NMR (500 MHz, CDCl₃) δ 8.59 (s, 1H), 8.19(s, 1H), 8.13 (s, 1H), 8.02 (s, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.67(d, J=8.0 Hz, 1H), 6.93 (s, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.85 (d, J=8.5Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 5.40 (s, 2H), 5.03 (s, 2H), 4.30 (m,1H), 3.94 (s, 3H), 3.82 (s, 3H), 3.31-3.28 (m, 2H), 2.84-2.80 (m, 2H),2.24-2.22 (m, 2H), 2.04-1.97 (m, 2H) ppm; (M+1)=526.

Example 3-20: Synthesis of3-(3-Methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridineExample 3-20-1: Preparation of Tert-butyl3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzylcarbamate

To a stirred solution of tert-butyl 4-hydroxy-3-methoxybenzylcarbamate(21.02 g, 82.99 mmol) in acetonitrile (250 mL) was added potassiumcarbonate (30.61 g, 221.5 mmol) and 5-(chloromethyl)-2-methylpyridinehydrochloride (16.25 g, 91.29 mmol). The resulting mixture was heated toreflux. After 63 h, the brown suspension was allowed to cool to roomtemperature and was diluted with water (1000 mL). The mixture wasextracted with dichloromethane (3×250 mL). The combined organic phaseswere dried over magnesium sulfate, filtered, and concentrated to provide31.59 g (>100%) of tert-butyl3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzylcarbamate as a brownoil.

Example 3-20-2: Preparation of(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)phenyl)methanamine

To a stirred solution of tert-butyl3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzylcarbamate (29.74 g,82.97 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid(50 mL, 649.0 mmol). The resulting brown solution was allowed to stir atroom temperature. After 2 h, the reaction mixture was concentrated todryness, and the residue was dissolved in water (250 mL). The acidicsolution was extracted with diethyl ether (2×125 mL; organic phasesdiscarded). The aqueous phase was then made basic with concentratedammonium hydroxide. The basic aqueous phase was then extracted withdichloromethane (3×100 mL). The combined organic phases were dried overmagnesium sulfate, filtered, and concentrated to provide 19.22 g (90%)of (3-methoxy-4-((6-methylpyridin-3-yl)methoxy)phenyl)methanamine asbrown solid.

Example 3-20-3: Preparation of5-iodo-N-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-3-nitropyridin-2-amine

To a stirred solution of(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)phenyl)methanamine (7.30 g,28.26 mmol) in acetonitrile (200 mL) was added2-chloro-5-iodo-3-nitropyridine (8.44 g, 29.67 mmol) andN,N-diisopropylethylamine (5.48 g, 42.39 mmol). The brown mixture washeated to reflux. After 5 h, the brown mixture was allowed to cool toroom temperature and was diluted with water (600 mL). The resultingprecipitate was isolated by filtration and washed with water (200 mL).The moist solids were dissolved in ethyl acetate (300 mL), and thissolution was washed with water (100 mL). The organic phase was driedover magnesium sulfate, filtered, and concentrated to provide 13.57 g(95%) of5-iodo-N-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-3-nitropyridin-2-amineas a bright yellow solid.

Example 3-20-4: Preparation of5-iodo-N2-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)pyridine-2,3-diamine

To a stirred suspension of5-iodo-N-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-3-nitropyridin-2-amine(13.57 g, 26.80 mmol) in acetic acid (100 mL) was added iron powder(8.10 g, 145.0 mmol). The bright yellow suspension was gradually warmedto 90° C. After 30 min of heating, the dark brown reaction mixture wasallowed to cool to room temperature and was diluted with ethyl acetate(400 mL). The mixture was filtered through Celite with the aid ofadditional ethyl acetate (100 mL). The filtrate was then washed withwater (2×150 mL) and 1N sodium hydroxide solution (2×200 mL). Theorganic phase was dried over magnesium sulfate, filtered, andconcentrated to provide 6.97 g (55%) of5-iodo-N2-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)pyridine-2,3-diamineas a brown solid.

Example 3-20-5: Preparation of6-iodo-3-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine

To a stirred suspension of5-iodo-N2-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)pyridine-2,3-diamine(6.98 g, 14.65 mmol) in ethanol (100 mL) was added triethyl orthoformate(3.56 g, 24.02 mmol) and p-toluenesulfonic acid monohydrate (0.050 g,0.26 mmol). As the resulting mixture was warmed to reflux, the solidsgradually dissolved to provide a brown solution. After 90 min, thereaction mixture was allowed to cool to room temperature, and themixture was concentrated to provide 7.91 g of a brown oil.Chromatographic purification (Combi-Flash, 220 g SiO2 gold column, 1-5%methanol/dichloromethane elute) afforded 5.22 g (73%) of6-iodo-3-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridineas a tan solid.

A portion of this material was used to prepare Example 3-20 using theprocedure outlined for the synthesis of Example 3-19: ¹H NMR (500 MHz,CDCl₃) δ 8.58 (d, J=1.5 Hz, 1H), 8.53 (d, J=2.0 Hz, 1H), 8.12 (d, J=2.0Hz, 1H), 8.00 (s, 1H), 7.83 (s, 1H), 7.74 (s, 1H), 7.66 (dd, J=8.0, 2.0Hz, 1H), 7.15 (d, J=8.5 Hz, 1H), 6.92 (d, J=1.0 Hz, 1H), 6.86-6.83 (m,2H), 5.39 (s, 2H), 5.08 (s, 2H), 4.31-4.26 (m, 1H), 3.81 (s, 3H),3.29-3.26 (m, 2H), 2.82-2.77 (m, 2H), 2.55 (s, 3H), 2.23-2.22 (m, 2H),2.01-1.92 (m, 2H) ppm; (M+1)=510.

Example 3-21: Synthesis of3-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazoleExample 3-21-1: Preparation of3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile

To a stirred solution of6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine(1.00 g, 1.99 mmol) in N,N-dimethylformamide (15 mL) was added copper(I)cyanide (0.53 g, 6.00 mmol). The mixture was heated to 150° C. After 5h, the mixture was allowed to cool to room temperature and wasconcentrated. The residue was purified by silica gel chromatography (2%methanol/dichloromethane elute) to give 0.53 g (66%) of3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrileas a yellow solid.

Example 3-21-2: Preparation ofN′-hydroxy-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine-6-carboximidamide

To a stirred solution of3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile(0.53 g, 1.32 mmol) in ethanol was added hydroxylamine solution (50%weight in water, 0.1 mL). The mixture was heated to 100° C. After 1 h,the mixture was concentrated to provide 0.66 g (>100%) ofN-hydroxy-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine-6-carboximidamideas a white solid.

Example 3-21-3: Preparation of tert-butyl4-(3-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate

To a stirred solution ofN-hydroxy-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine-6-carboximidamide(0.38 g, 0.75 mmol) in N,N-dimethylformamide (10 mL) was added1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0.21 g, 0.92 mmol),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (0.35 g, 0.92 mmol) andN,N-diisopropylethylamine (0.19 g, 1.50 mmol). The reaction mixture wasstirred at room temperature. After 1 h, the mixture was diluted withethyl acetate and brine. The organic phase was separated, dried overmagnesium sulfate, filtered, and concentrated. The residue was dissolvedin 1,4-dioxane (20 mL) and heated to 85° C. After 16 h, the reactionmixture was allowed to cool to room temperature and was concentrated.The crude product was purified by silica gel chromatography (2%methanol/dichloromethane elute) to provide 0.14 g (25%) of tert-butyl4-(3-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylateas a yellow solid.

Example 3-21-4: Preparation of3-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazole

To a stirred solution of tert-butyl4-(3-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate(0.14 g, 0.22 mmol) in dichloromethane (20 mL) was added trifluoroaceticacid (0.20 g, 1.79 mmol). The reaction mixture was allowed to stir atroom temperature. After 1 h, the mixture was diluted with cold saturatedsodium carbonate solution. The phases were separated, and the aqueousphase extracted with dichloromethane. The combined organic phases werewashed with brine, dried over magnesium sulfate, filtered, andconcentrated. The residue was purified by Prep-HPLC to provide 0.067 g(57%) of the product as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.02(d, J=1.5 Hz, 1H), 8.75 (s, 1H), 8.58 (d, J=2.0 Hz, 1H), 8.21 (d, J=2.0Hz, 1H), 7.75 (dd, J=8.5, 2.0 Hz, 1H), 7.16 (d, J=1.5 Hz, 1H), 7.03 (d,J=8.0 Hz, 1H), 6.89 (dd, J=8.0, 2.0 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H),5.48 (s, 2H), 4.98 (s, 2H), 3.84 (s, 3H), 3.74 (s, 3H), 3.26-3.21 (m,1H), 3.02-3.00 (m, 2H), 2.65-2.61 (m, 2H), 2.02-2.00 (m, 2H), 1.75-1.67(m, 2H) ppm; (M+1)=528.

Example 3-22: Synthesis of3-(1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazole

3-(1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazolewas prepared from5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazoleusing the procedure outlined for Example 3-21: ¹H NMR (500 MHz, DMSO-d₆)δ 8.55 (s, 1H), 8.26 (s, 1H), 8.21 (d, J=2.0 Hz, 1H), 7.89 (d, J=8.5 Hz,1H), 7.77-7.73 (m, 2H), 7.12 (d, J=1.5 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H),6.87-6.83 (m, 2H), 5.46 (s, 2H), 4.98 (s, 2H), 3.85 (s, 3H), 3.74 (s,3H), 3.22-3.17 (m, 1H), 3.02-3.00 (m, 2H), 2.65-2.61 (m, 2H), 2.01-1.99(m, 2H), 1.73-1.68 (m, 2H) ppm; (M+1)=527.

Example 3-23: Synthesis of2-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,3,4-oxadiazole

2-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4-yl)-1,3,4-oxadiazolewas prepared from6-iodo-3-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridineaccording to the procedure outlined for the synthesis of Example 3-7: ¹HNMR (500 MHz, CD₃D) δ 9.13 (d, J=1.5 Hz, 1H), 8.67-8.62 (m, 2H), 8.15(d, J=1.5 Hz, 1H), 7.76 (dd, J=8.5, 2.0 Hz, 1H), 7.15 (d, J=1.5 Hz, 1H),7.01-6.95 (m, 2H), 6.80 (d, J=9.0 Hz, 1H), 5.53 (s, 2H), 5.01 (s, 2H),3.90 (s, 3H), 3.82 (s, 3H), 3.51-3.46 (m, 3H), 3.21-3.16 (m, 2H),2.44-2.41 (m, 2H), 2.18-2.09 (m, 2H) ppm; (M+1)=528.

Example 3-24: Synthesis of2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-1,2,3-triazol-4-yl)propan-2-amine

2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-1,2,3-triazol-4-yl)propan-2-aminewas prepared from6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridineand 2-methylbut-3-yn-2-amine according to the procedure described forthe synthesis of Example 3-6: ¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (d, J=2.3Hz, 1H), 8.76 (s, 1H), 8.65 (s, 1H), 8.56 (d, J=2.3 Hz, 1H), 8.21 (d,J=2.5, 1H), 7.74 (dd, J=8.5, 2.5 Hz, 1H), 7.16 (d, J=2.0 Hz, 1H), 7.02(d, J=8.2 Hz, 1H), 6.88 (dd, J=8.2, 2.0 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H),5.48 (s, 2H), 4.98 (s, 2H), 3.84 (s, 3H), 3.74 (s, 3H), 1.98 (br s, 2H),1.46 (s, 6H) ppm; (M+1)=501.

Example 3-25: Synthesis of3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-3H-imidazo[4,5-b]pyridine

3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-3H-imidazo[4,5-b]pyridinewas prepared from6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridineaccording to the procedure described for the synthesis of Example 3-6:¹H NMR (400 MHz, DMSO-d₆) δ 8.91 (d, J=2.3 Hz, 1H), 8.76 (s, 1H), 8.64(s, 1H), 8.56 (d, J=2.3 Hz, 1H), 8.20 (d, J=1.7 Hz, 1H), 7.74 (dd,J=8.5, 2.4 Hz, 1H), 7.16 (d, J=2.0 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H), 6.87(dd, J=8.3, 2.0 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 5.48 (s, 2H), 4.97 (s,2H), 3.84 (s, 3H), 3.73 (s, 3H), 3.22-3.16 (m, 1H), 2.98-2.79 (m, 2H),2.65-2.52 (m, 2H), 2.14-2.03 (m, 1H), 1.71-1.43 (m, 3H) ppm; (M+1)=527.

Example 3-26: Synthesis of1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-amine

1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-aminewas prepared from5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-2-amineand 1-methylpiperazine according to the procedure described for thesynthesis of Example 3-13: ¹H NMR (500 MHz, CDCl₃) δ 8.19 (d, J=2.0 Hz,1H), 7.67 (dd, J=8.5, 3.0 Hz, 1H), 7.09 (d, J=1.5 Hz, 1H), 6.99 (d,J=8.5 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.79-6.75 (m, 2H), 6.72 (s, 1H),6.67 (d, J=8.5 Hz, 1H), 5.03 (s, 2H), 5.02 (s, 2H), 3.94 (s, 3H), 3.77(s, 3H), 3.22-3.17 (m, 4H), 2.65-2.59 (m, 4H), 2.37 (s, 3H) ppm;(M+1)=489.

Example 3-27: Synthesis of1-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazoleExample 3-27-1: Preparation of5-((4-bromo-5-fluoro-2-methoxyphenoxy)methyl)-2-methoxypyridine

To a stirred solution of 4-bromo-5-fluoro-2-methoxyphenol (2.82 g, 12.25mmol) in N,N-dimethylformamide (50 mL) was added5-(chloromethyl)-2-methoxypyridine hydrochloride (2.50 g, 12.86 mmol)and potassium carbonate (5.08 g, 36.75 mmol). The reaction mixture washeated to 100° C. After 2 h, the mixture was allowed to cool to roomtemperature and was diluted with water. The mixture was extracted withethyl acetate (3×25 mL). The combined organic phases were washed withbrine, dried over magnesium sulfate, filtered, and concentrated.Chromatographic purification (0-33% ethyl acetate/hexanes elute)afforded 2.76 g (66%) of5-((4-bromo-5-fluoro-2-methoxyphenoxy)methyl)-2-methoxypyridine as anoil.

Example 3-27-2: Preparation of2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzonitrile

To a stirred solution of5-((4-bromo-5-fluoro-2-methoxyphenoxy)methyl)-2-methoxypyridine (4.57 g,13.36 mmol) in N,N-dimethylformamide (50 mL) was added copper(I) cyanide(3.59 g, 40.07 mmol). The mixture was heated to 150° C. After 16 h, themixture was allowed to cool to room temperature and was diluted withdichloromethane. The mixture was filtered through Celite. The filtratewas washed with water and brine, dried over magnesium sulfate, filtered,and concentrated. Chromatographic purification (Combi-Flash, 80 g SiO2column, 1-5% methanol/dichloromethane elute) afforded 3.25 g (84%) of2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzonitrile as anoff-white solid.

Example 3-27-3: Preparation of(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine

To a 0° C. stirred solution of2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzonitrile (3.25g, 11.27 mmol) in tetrahydrofuran (50 mL) was added (in three portions)lithium aluminum hydride (0.86 g, 22.55 mmol). Mild gas evolution wasnoted upon each addition, and the color of the reaction mixture becameolive-green. After 1.5 h, the mixture was quenched by the slow additionof water (1.0 mL), 15% sodium hydroxide solution (1.0 mL), and water(3.0 mL). The resulting off-white suspension was allowed to stir at 0°C. After 15 min, the mixture was filtered through Celite with the aid ofethyl acetate. The filtrate was concentrated to provide 1.91 g (58%) of(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamineas a crude oil.

Example 3-27-4: Preparation ofN¹-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-4-iodo-2-nitroaniline

To a stirred solution of(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine(0.89 g, 3.04 mmol) in acetonitrile (15 mL) was added1-fluoro-4-iodo-2-nitrobenzene (0.89 g, 3.35 mmol) andN,N-diisopropylethylamine. The resulting yellow solution was heated toreflux. After 16 h, the mixture was allowed to cool to room temperatureand was diluted with water. The mixture was extracted with ethyl acetate(3×25 mL). The combined organic phases were washed with brine, driedover magnesium sulfate, filtered, and concentrated. Chromatographicpurification (Combi-Flash, 40 g SiO2 column, 0-33% ethyl acetate/hexaneselute) afforded 0.38 g (23%) ofN-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-4-iodo-2-nitroanilineas a solid.

Example 3-27-5: Preparation ofN-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-4-iodobenzene-1,2-diamine

To a stirred solution ofN-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-4-iodo-2-nitroaniline(0.38 g, 0.70 mmol) in tetrahydrofuran (10 mL), methanol (5 mL), andwater (1 mL) was added ammonium chloride (0.30 g, 5.64 mmol) and iron(II) sulfate heptahydrate (0.69 g, 2.47 mmol). The bright orangesuspension was treated with zinc (0.16 g, 2.47 mmol). The mixture wasgradually warmed to reflux. After 3.5 h, the color of the reactionmixture had turned from orange to olive-green. At this point thereaction mixture was allowed to cool to room temperature. The mixturewas filtered through Celite, and the filtercake was washed withchloroform (250 mL). The filtrate was washed with 5N ammonium hydroxidesolution (75 mL). The organic phase was dried over magnesium sulfate,filtered, and concentrated to afford 0.36 g (100%) ofN¹-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-4-iodobenzene-1,2-diamineas a tan solid.

Example 3-27-6: Preparation of1-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodo-1H-benzo[d]imidazole

To a stirred solution ofN¹-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-4-iodobenzene-1,2-diamine(0.36 g, 0.70 mmol) in ethanol (10 mL) was added triethyl orthformate(0.31 g, 2.11 mmol) and p-toluenesulfonic acid (0.007 g, 0.035 mmol).The reaction mixture was heated to reflux. After 30 min, the brownsolution was allowed to cool to room temperature and was concentrated.The residue was partitioned between water and dichloromethane. Thephases were separated, and the aqueous phase extracted withdichloromethane. The combined organic phases were washed with water andbrine, dried over magnesium sulfate, filtered, and concentrated.Chromatographic purification (Combi-Flash, 12 g SiO₂ column, 1-5%methanol/dichloromethane elute) afforded 0.25 g (68%) of1-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodo-1H-benzo[d]imidazoleas a tan solid.

Example 3-27-7: Preparation of1-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazole

To a stirred suspension of1-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodo-1H-benzo[d]imidazole(0.20 g, 0.39 mmol) in dimethyl sulfoxide (4 mL) was added1-methylpiperazine (0.039 g, 0.39 mmol), copper(I) iodide (0.009 g,0.046 mmol), potassium carbonate (0.19 g, 1.35 mmol), and L-proline(0.010 g, 0.092 mmol). The light yellow reaction mixture was heated to120° C. After 16 h, the reaction mixture was allowed to cool to roomtemperature and was diluted with 3 N ammonium hydroxide solution (20mL). The mixture was extracted with dichloromethane. The organic phasewas washed with water (2×15 mL), brine, dried over magnesium sulfate,filtered, and concentrated. Chromatographic purification (CombiFlash, 40g SiO₂ column, 1-5% methanol/dichloromethane elute) provided 0.062 g ofimpure material. Subsequent re-purification via Prep-HPLC afforded 0.030g (16%) of the product as a solid: ¹H NMR (400 MHz, CDCl₃) δ 8.19 (d,J=2.0 Hz, 1H), 7.88 (s, 1H), 7.65 (dd, J=8.5, 2.5 Hz, 1H) 7.33 (d, J=2.1Hz, 1H), 7.29-7.22 (m, 2H), 7.07-6.99 (m, 1H), 6.78-6.69 (m, 2H), 6.56(d, J=7.1 Hz, 1H), 5.30 (s, 2H), 5.00 (s, 2H), 3.94 (s, 3H), 3.69 (s,3H), 3.25-3.18 (m, 4H), 2.71-2.59 (m, 4H), 2.39 (s, 3H) ppm; (M+1)=492.

Example 3-28: Synthesis of3-(3-Ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridineExample 3-28-1: Preparation of3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzaldehyde

To a stirred solution of 3-ethoxy-4-hydroxybenzaldehyde (2.75 g, 16.55mmol) in acetonitrile (75 mL) was added5-(chloromethyl)-2-methoxypyridine hydrochloride (3.37 g, 17.38 mmol)and potassium carbonate (9.15 g, 66.20 mmol). The mixture was heated toreflux. After 3 h, the yellow mixture was allowed to cool to roomtemperature and was diluted with water (400 mL), resulting in theformation of a precipitate. The solids were isolated by filtration andwashed with water (50 mL). The filtrate was extracted with chloroform(2×100 mL). The organic phases were combined with the previouslyisolated solids. The resulting solution was dried over magnesiumsulfate, filtered, and concentrated to provide 3.40 g (72%) of3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzaldehyde as a yellowsolid.

Example 3-28-2: Preparation of3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzaldehyde oxime

To a stirred solution of3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzaldehyde (3.40 g, 11.83mmol) in methanol (50 mL), pyridine (1.5 mL), and water (5 mL) was addedhydroxylamine hydrochloride (1.23 g, 17.75 mmol). The reaction mixturewas heated to reflux. After 2 h, the colorless solution was allowed tocool to room temperature and was concentrated. The residue was suspendedin water (50 mL) and filtered. The solids were washed with water andthen dissolved in ethyl acetate (150 mL). The solution was dried overmagnesium sulfate, filtered, and concentrated to provide 3.05 g (85%) of3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzaldehyde oxime as anoff-white solid.

Example 3-28-3: Preparation of(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine

To a stirred solution of3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzaldehyde oxime (3.05 g,10.09 mmol) in acetic acid (25 mL) was added zinc (3.30 g, 50.44 mmol).The resulting mixture was heated to 65° C. After 2 h, the graysuspension was allowed to cool to room temperature and was diluted withethyl acetate (150 mL). The mixture was filtered through Celite with theaid of additional ethyl acetate (50 mL). The filtrate was diluted withwater (50 mL) and made basic by the addition of concentrated ammoniumhydroxide solution (˜30 mL). The phases were separated, and the aqueousphase was extracted with ethyl acetate (50 mL). The combined organicphases were dried over magnesium sulfate, filtered, and concentrated toprovide 2.75 g (95%) of(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine as ayellow oil.

Example 3-28-4: Preparation ofN-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodo-3-nitropyridin-2-amine

To a stirred solution of(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine (2.75 g,9.54 mmol) in acetonitrile (50 mL) was added2-chloro-5-iodo-3-nitropyridine (2.85 g, 10.01 mmol) andN,N-diisopropylethylamine (1.85 g, 14.31 mmol). The resulting yellowmixture was heated to reflux. After 3 h, the red-brown solution wasallowed to cool to room temperature, resulting in the formation of aprecipitate. The solids were isolated by filtration and washed withwater (200 mL). The moist solids were dissolved in dichloromethane (100mL), and a small amount of water separated and was removed. The solutionwas dried over magnesium sulfate, filtered, and concentrated to provide4.34 g (85%) ofN-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodo-3-nitropyridin-2-amineas an orange solid.

Example 3-28-5: Preparation ofN²-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodopyridine-2,3-diamine

To a stirred suspension ofN-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodo-3-nitropyridin-2-amine(4.34 g, 8.09 mmol) in acetic acid (25 mL) was added iron powder (2.26g, 40.46 mmol). The reaction mixture was heated to 90° C. After 15 min,the reaction mixture became a gray-brown suspension. The mixture wasallowed to cool to room temperature and was diluted with ethyl acetate(200 mL). The mixture was filtered through Celite with the aid ofadditional ethyl acetate (50 mL). The filtrate was washed with water(2×50 mL) and then with 1N sodium hydroxide solution (3×50 mL). Theorganic phase was dried over magnesium sulfate, filtered, andconcentrated to provide 3.99 g (97%) ofN²-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodopyridine-2,3-diamineas a tan solid.

Example 3-28-6: Preparation of3-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-iodo-3H-imidazo[4,5-b]pyridine

To a stirred suspension ofN²-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodopyridine-2,3-diamine(3.99 g, 7.88 mmol) in ethanol (50 mL) was added triethyl orthoformate(2.67 g, 18.02 mmol) and p-toluenesulfonic acid monohydrate (0.075 g,0.39 mmol). As the mixture was heated to reflux, a brown solution wasobtained. After 30 min, the mixture was allowed to cool to roomtemperature, resulting in the formation of a precipitate. The solidswere isolated by filtration, washed with ethanol, and dried to provide2.50 g (61%) of3-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-iodo-3H-imidazo[4,5-b]pyridineas a tan solid.

Example 3-28-7: Preparation of3-(3-Ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine

To a stirred suspension of3-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-iodo-3H-imidazo[4,5-b]pyridine(0.37 g, 0.71 mmol) in dimethylsulfoxide was added 1-methylpiperazine(0.086 g, 0.85 mmol), copper(I) iodide (0.033 g, 0.18 mmol), L-proline(0.041 g, 0.35 mmol), and potassium carbonate (0.24 g, 1.77 mmol). Themixture was degassed under vacuum/backfilled with N₂ (×3) and thenheated to 120° C. After 16 h, the dark brown mixture was allowed to coolto room temperature and was diluted with 5N ammonium hydroxide solution(50 mL). The mixture was extracted with dichloromethane (3×50 mL). Thecombined organic phases were dried over magnesium sulfate, filtered, andconcentrated to provide 0.36 g of a brown oil. Chromatographicpurification (Combi-Flash, 12 g SiO₂ gold column, 5-10% 2M ammonia inmethanol/dichloromethane elute) afforded 0.14 g (41%) of the product asan orange solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (s, 1H), 8.22-8.19 (m,2H), 7.73 (dd, J=8.5, 2.4 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.08 (d,J=2.0 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H), 6.86-6.76 (m, 2H), 5.33 (s, 2H),4.97 (s, 2H), 3.97 (q, J=6.9 Hz, 2H), 3.84 (s, 3H), 3.17-3.08 (m, 4H),2.53-2.45 (m, 4H), 2.23 (s, 3H), 1.28 (t, J=6.9 Hz, 3H); (M+1)=489.

Example 3-29: Synthesis of1-(1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-4-methylpiperazin-2-one

1-(1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-4-methylpiperazin-2-onewas prepared from5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole(Step 5, Example 6) and 4-methylpiperazin-2-one using the procedureoutlined for Example 3-14: ¹H NMR (500 MHz, CDCl₃) δ 8.21 (d, J=2.0 Hz,1H), 7.97 (s, 1H), 7.70-7.68 (m, 2H), 7.34 (d, J=8.5 Hz, 1H), 7.22 (dd,J=8.5, 1.5 Hz, 1H), 6.90-6.89 (m, 1H), 6.78-6.74 (m, 3H), 5.29 (s, 2H),5.05 (s, 2H), 3.95 (s, 3H), 3.81 (s, 3H), 3.79 (t, J=5.5 Hz, 2H), 3.35(s, 2H), 2.86 (t, J=5.5 Hz, 2H), 2.46 (s, 3H) ppm; (M+1)=488.

Example 3-30: Synthesis of3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(5-methyl-1-azabicyclo[3.2.1]oct-6-en-7-yl)-3H-imidazo[4,5-b]pyridineExample 3-30-1: Preparation of tert-butyl3-ethynyl-3-methylpiperidine-1-carboxylate

To a stirred solution of tert-butyl3-formyl-3-methylpiperidine-1-carboxylate (2.10 g, 9.25 mmol) inmethanol (40 mL) was added potassium carbonate (2.76 g, 20.00 mmol). Themixture was treated with dimethyl 1-diazo-2-oxopropylphosphonate (2.11g, 11.00 mmol), and the resulting mixture was allowed to stir at roomtemperature. After 2 h, the mixture was concentrated, diluted withwater, and extracted with ethyl acetate. The organic phase was washedwith brine, dried over magnesium sulfate, filtered, and concentrated.The residue was purified by silica gel chromatography (6% ethylacetate/petroleum ether elute) to afford 1.50 g (73%) of tert-butyl3-ethynyl-3-methylpiperidine-1-carboxylate as a pale yellow oil.

Example 3-30-2: Preparation of 3-ethynyl-3-methylpiperidinehydrochloride

To a stirred solution of tert-butyl3-ethynyl-3-methylpiperidine-1-carboxylate (0.50 g, 2.24 mmol) indichloromethane (10 mL) was added a solution of hydrogen chloride in1,4-dioxane (3.0M, 5.0 mL, 15.00 mmol). The resulting solution wasallowed to stir at room temperature. After 2 h, the mixture wasconcentrated to provide 0.34 g (95%) of 3-ethynyl-3-methylpiperidinehydrochloride (340 mg, 95%) as a white solid.

Example 3-30-3: Preparation of3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(5-methyl-1-azabicyclo[3.2.1]oct-6-en-7-yl)-3H-imidazo[4,5-b]pyridine

To a stirred suspension of6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine(Step 3, Example 19, 0.20 g, 0.40 mmol) in tetrahydrofuran (3.0 mL) wasadded 3-ethynyl-3-methylpiperidine hydrochloride (0.13 g, 1.00 mmol),bis(triphenylphosphine)palladium(II) chloride (0.055 g, 0.078 mmol),copper(I) iodide (0.030 g, 0.16 mmol), and piperidine (0.17 g, 2.00mmol). The mixture was heated to 60° C. in a microwave reactor. After 30min, the mixture was allowed to cool to room temperature and wasfiltered through Celite. The filtrate was concentrated, and the residuewas purified by Prep-HPLC to afford 0.020 g (10%) of the product as ayellow solid: ¹H NMR (500 MHz, CDCl₃) δ 8.77 (d, J=2.0 Hz, 1H), 8.29 (d,J=2.0 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 8.01 (s, 1H), 7.68 (dd, J=8.0,2.0 Hz, 1H), 6.94-6.76 (m, 4H), 6.02 (s, 1H), 5.40 (s, 2H), 5.04 (s,2H), 3.95 (s, 3H), 3.82 (s, 3H), 3.22 (d, J=8.5 Hz, 1H), 2.94-2.86 (m,2H), 2.80 (d, J=9.5 Hz, 1H), 1.91-1.85 (m, 1H), 1.60-1.46 (m, 3H), 1.16(s, 3H) ppm; (M+1)=498.

Example 3-31: Synthesis of1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(5-methyl-1-azabicyclo[3.2.1]oct-6-en-7-yl)-1H-benzo[d]imidazole

1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(5-methyl-1-azabicyclo[3.2.1]oct-6-en-7-yl)-1H-benzo[d]imidazolewas prepared from5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazoleand 3-ethynyl-3-methylpiperidine hydrochloride using the procedureoutlined for the synthesis of Example 3-30: ¹H NMR (500 MHz, CDCl₃) δ8.22-8.21 (m, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.69 (dd, J=8.5, 2.5 Hz,1H), 7.60 (d, J=8.5 Hz, 1H), 7.28-7.26 (m, 1H, partially obscured byCHCl₃), 6.89 (d, J=8.5 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.75-6.73 (m,2H), 5.93 (s, 1H), 5.28 (s, 2H), 5.04 (s, 2H), 3.95 (s, 3H), 3.80 (s,3H), 3.21 (dd, J=9.5, 1.5 Hz, 1H), 2.92-2.90 (m, 2H), 2.79 (d, J=10.0Hz, 1H), 1.87-1.83 (m, 1H), 1.57-1.43 (m, 3H), 1.14 (s, 3H) ppm;(M+1)=497.

Example 3-32: Synthesis of7-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1-azabicyclo[3.2.1]oct-6-en-5-olExample 3-32-1: Preparation of 3-ethynylpiperidin-3-ol Hydrochloride

3-Ethynylpiperidin-3-ol hydrochloride was prepared from tert-butyl3-ethynyl-3-hydroxypiperidine-1-carboxylate and hydrogen chloride usingthe procedure outlined in Example 3-30.

Example 3-32-2: Preparation of7-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1-azabicyclo[3.2.1]oct-6-en-5-ol

7-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1-azabicyclo[3.2.1]oct-6-en-5-olwas prepared from6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridineand 3-ethynylpiperidin-3-ol hydrochloride using the procedure outlinedfor the synthesis of Example 3-30: ¹H NMR (500 MHz, CDCl₃) δ 8.76 (d,J=2.0 Hz, 1H), 8.29 (d, J=1.5 Hz, 1H), 8.20 (d, J=2.7 Hz, 1H), 8.04 (s,1H), 7.68 (dd, J=8.5, 2.7 Hz, 1H), 6.93 (d, J=2.0 Hz, 1H), 6.89 (d,J=8.0 Hz, 1H), 6.85 (dd, J=8.0, 1.5 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H),6.19 (s, 1H), 5.41 (s, 2H), 5.05 (s, 2H), 3.95 (s, 3H), 3.83 (s, 3H),3.43-3.41 (m, 1H), 2.94-2.91 (m, 1H), 2.85-2.81 (m, 2H), 1.91-1.84 (m,2H), 1.74-1.71 (m, 2H) ppm; (M+1)=500.

Example 3-33: Synthesis of7-(1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-1-azabicyclo[3.2.1]oct-6-en-5-ol

7-(1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-1-azabicyclo[3.2.1]oct-6-en-5-olwas prepared from5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazoleand 3-ethynylpiperidin-3-ol hydrochloride using the procedure outlinedfor the synthesis of Example 3-30: ¹H NMR (500 MHz, CDCl₃) δ 8.21 (d,J=2.5 Hz, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.69 (dd, J=8.5, 2.5 Hz, 1H),7.59 (dd, J=8.5, 1.0 Hz, 1H), 7.29-7.26 (m, 1H, partially obscured byCHCl₃), 6.89 (d, J=9.0 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.75-6.73 (m,2H), 6.09 (s, 1H), 5.29 (s, 2H), 5.05 (s, 2H), 3.95 (s, 3H), 3.80 (s,3H), 3.41-3.39 (m, 1H), 2.92-2.83 (m, 3H), 1.89-1.81 (m, 3H), 1.71-1.67(m, 1H) ppm; (M+1)=499.

Example 3-34: Synthesis of3-(3-methoxy-4-(1-(6-methoxypyridin-3-yl)propoxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amineExample 3-34-1: Preparation of EthylN—({5-iodo-2-[({3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl}methyl)amino]pyridin-3-yl}carbamothioyl)carbamate

To a stirred solution of5-iodo-N²-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyridine-2,3-diamine(Example 3-16-2) (2.00 g, 4.07 mmol) and triethylamine (1.30 g, 1.8 mL,12.85 mmol) in tetrahydrofuran (20 mL) was added O-ethylcarbonisothiocyanatidate (1.07 g, 8.20 mmol). The reaction mixture wasallowed to stir at room temperature. After 3 h, the mixture wasfiltered, and the filtrate was concentrated to provide 2.30 g of ethylN—({5-iodo-2-[({3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl}methyl)amino]pyridin-3-yl}carbamothioyl)carbamateas a yellow oil.

Example 3-34-2: Preparation of Ethyl(6-iodo-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate

To a stirred solution of ethylN—({5-iodo-2-[({3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl}methyl)amino]pyridin-3-yl}carbamothioyl)carbamate(2.30 g, 3.69 mmol) and triethylamine (1.30 g, 1.8 mL, 12.85 mmol) intetrahydrofuran (20 mL) was added benzenesulfonyl chloride (0.93 g, 5.27mmol). The resulting mixture was allowed to stir at room temperature.After 12 h, a precipitate had formed. The mixture was filtered, and thefiltercake was washed with water (2×10 mL) and methanol (10 mL). Thesolids were dried to provide 1.50 g (69%) of ethyl(6-iodo-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamateas a brown solid.

Example 3-34-3: Preparation of Ethyl(3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate

To a stirred solution of ethyl(6-iodo-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate(11.80 g, 20.05 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(5.00 g, 24.03 mmol) in N,N-dimethylformamide (100 mL) and 2M aqueoussodium carbonate solution (10 mL) was added(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.87 g,1.19 mmol). The resulting mixture was heated to 80° C. under a nitrogenatmosphere. After 4 h, the mixture was allowed to cool to roomtemperature and was filtered through Celite. The filtrate was dilutedwith water (150 mL) and extracted with ethyl acetate (3×200 mL). Thecombined organic phases were washed with water (300 mL) and brine (2×300mL), dried over sodium sulfate, filtered, and concentrated.Chromatographic purification (silica gel, 5% methanol in dichloromethaneelute) afforded 2.50 g (23%) of ethyl(3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamateas a gray solid.

Example 3-34-4: Preparation of Ethyl(3-(4-hydroxy-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate

To a stirred solution of ethyl(3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate(2.50 g, 4.61 mmol) in dichloromethane (100 mL) at 0° C. was addedtrifluoroacetic acid (4.47 g, 3.0 mL, 39.18 mmol). The resulting mixturewas allowed to stir at 0° C. After 2 h, the mixture was treated with 2Mpotassium carbonate solution to adjust the pH to ˜9. The basic mixturewas extracted with 1:1 methanol/dichloromethane solution (2×50 mL). Thecombined organic phases were washed with brine (2×50 mL), dried oversodium sulfate, filtered, and concentrated to provide 1.80 g (93%) ofethyl(3-(4-hydroxy-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamateas a white solid.

Example 3-34-5: Preparation of 5-(1-chloropropyl)-2-methoxypyridine

To a stirred solution of 1-(6-methoxypyridin-3-yl)propan-1-ol (1.67 g,9.99 mmol) in dichloromethane (30 mL) at 0° C. was added thionylchloride (2.46 g, 1.5 mL, 20.68 mmol). The cooling bath was removed, andthe mixture was allowed to warm to room temperature. After 1 h, thereaction was quenched by the addition of saturated aqueous sodiumbicarbonate solution. The phases were separated, and the organic phasewas washed with brine (20 mL), dried over sodium sulfate, filtered, andconcentrated to provide 1.50 g (81%) of5-(1-chloropropyl)-2-methoxypyridine as a yellow oil.

Example 3-34-6: Preparation of3-(3-methoxy-4-(1-(6-methoxypyridin-3-yl)propoxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

To a stirred solution of ethyl(3-(4-hydroxy-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate(0.300 g, 0.710 mmol) in tetrahydrofuran (20 mL) was added 5M aqueoussodium hydroxide solution (0.72 mL, 3.60 mmol). The resulting mixturewas allowed to stir at room temperature. After 2 h, the mixture wasconcentrated, and the residue was dissolved in N,N-dimethylformamide (10mL). The solution was treated with 5-(1-chloropropyl)-2-methoxypyridine(0.263 g, 1.42 mmol), and the resulting mixture was heated to 80° C.After 3 h, the mixture was allowed to cool to room temperature and wasdiluted with water (20 mL). The mixture was extracted with ethyl acetate(3×40 mL). The combined organic phases were dried over sodium sulfate,filtered, and concentrated to provide 0.26 g of a brown solid. The crudesolid was dissolved in ethylene glycol (6 mL) and water (2 mL). Thesolution was treated with potassium hydroxide (0.13 g, 2.32 mmol) andheated to 100° C. After 12 h, the mixture was allowed to cool to roomtemperature and was filtered through Celite. The filtrate wasconcentrated, and the residue was purified by prep-HPLC to afford 0.070g (30%) of the product as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ8.10-8.07 (m, 3H), 7.83 (s, 1H), 7.66-7.64 (m, 1H), 7.57 (d, J=1.5 Hz,1H), 7.04 (d, J=1.5 Hz, 1H), 6.86 (s, 2H), 6.77-6.74 (m, 2H), 6.58-6.57(m, 1H), 5.15-5.12 (m, 3H), 3.85 (s, 3H), 3.79 (s, 3H), 3.72 (s, 3H),1.95-1.90 (m, 1H), 1.78-1.74 (m, 1H), 0.85 (t, J=7.5 Hz, 3H) ppm;(M+1)=500.

Example 3-35: Synthesis of Additional Compounds from Ethyl(3-(4-hydroxy-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate

The following compounds were prepared from ethyl(3-(4-hydroxy-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamateusing the procedure described in Example 3-34-6 by employing theappropriate alkylating agent:

Example 3-35-1:3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

¹H NMR (500 MHz, DMSO-d₆) δ 8.21 (d, J=2.5 Hz, 1H), 8.12-8.11 (m, 2H),7.85 (s, 1H), 7.74 (dd, J=8.5, 2.0 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.10(d, J=1.5 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 6.89 (s, 2H), 6.83 (d, J=8.5Hz, 1H), 6.74 (dd, J=8.0, 1.5 Hz, 1H), 5.19 (s, 2H), 4.96 (s, 2H), 3.86(s, 3H), 3.84 (s, 3H), 3.71 (s, 3H) ppm; (M+1)=472.

Example 3-35-2:3-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.11-8.09 (m, 3H), 7.93 (d,J=8.0 Hz, 1H), 7.85 (s, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.14 (d, J=1.6 Hz,1H), 7.00-6.98 (m, 1H), 6.91 (s, 2H), 6.75-6.72 (m, 1H), 5.21-5.20 (m,4H), 3.86 (s, 3H), 3.74 (s, 3H) ppm; (M+1)=510.

Example 3-35-3:3-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine(RA09651030)

¹H NMR (500 MHz, MeOD-d₄) δ 8.17 (s, 1H), 7.98 (s, 1H), 7.83 (s, 1H),7.68-7.61 (m, 5H), 7.00 (d, J=1.5 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H),6.75-6.74 (m, 1H), 5.29 (s, 2H), 5.15 (s, 2H), 3.95 (s, 3H), 3.80 (s,3H) ppm; (M+1)=509.

Example 3-35-4:3-(4-((6-cyclopropylpyridin-3-yl)methoxy)-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine(RA09677155)

¹H NMR (500 MHz, DMSO-d₆) δ 8.42 (d, J=1.5 Hz, 1H), 8.11 (d, J=2.0 Hz,1H), 8.10 (s, 1H), 7.85 (s, 1H), 7.66 (dd, J=8.0, 2.5 Hz, 1H), 7.59 (d,J=2.5 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.10 (d, J=2.0 Hz, 1H), 6.97 (d,J=8.5 Hz, 1H), 6.89 (s, 2H), 6.73 (dd, J=8.0, 1.0 Hz, 1H), 5.19 (s, 2H),4.98 (s, 2H), 3.86 (s, 3H), 3.71 (s, 3H), 2.10-2.07 (m, 1H), 0.95-0.89(m, 4H) ppm; (M+1)=482.

Example 3-35-5:3-(3-methoxy-4-((2-methylthiazol-4-yl)methoxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

¹H NMR (500 MHz, DMSO-d₆) δ 8.11-8.10 (m, 2H), 7.85 (s, 1H), 7.59 (d,J=1.5 Hz, 1H), 7.48 (s, 1H), 7.11 (d, J=1.5 Hz, 1H), 7.00 (d, J=8.0 Hz,1H), 6.90 (s, 2H), 6.74-6.72 (m, 1H), 5.19 (s, 2H), 5.01 (s, 2H), 3.86(s, 3H), 3.72 (s, 3H) 2.64 (s, 3H) ppm; (M+1)=462.

Example 3-36: Synthesis of3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-phenyl-3H-imidazo[4,5-b]pyridin-2-amineExample 3-36-1: Preparation of Ethyl(3-(4-hydroxy-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5-b]pyridin-2-yl)carbamate

To a stirred solution of ethyl(6-iodo-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate(Example 3-34-2) (2.40 g, 4.08 mmol) in dichloromethane (50 mL) at 0° C.was added trifluoroacetic acid (4.47 g, 3.0 mL, 39.18 mmol). Theresulting mixture was allowed to stir at 0° C. After 2 h, the mixturewas treated with 2M potassium carbonate solution to adjust the pH to 9.The basic mixture was extracted with 1:1 methanol/dichloromethanesolution (3×50 mL). The combined organic phases were washed with brine(50 mL), dried over sodium sulfate, filtered, and concentrated toprovide 1.30 g (70%) of ethyl(3-(4-hydroxy-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5-b]pyridin-2-yl)carbamateas a light yellow solid.

Example 3-36-2: Preparation of Ethyl(6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate

To a stirred solution of ethyl(3-(4-hydroxy-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5-b]pyridin-2-yl)carbamate() (1.30 g, 2.78 mmol) and 5M aqueous sodium hydroxide solution (0.8 mL,4.00 mmol) in N,N-dimethylformamide (10 mL) and tetrahydrofuran (10 mL)was added 5-(chloromethyl)-2-methoxypyridine (0.567 g, 3.60 mmol). Theresulting mixture was allowed to stir at room temperature. After 2 h,the mixture was diluted with brine (40 mL) and extracted with ethylacetate (3×40 mL). The combined organic phases were dried over sodiumsulfate, filtered, and concentrated to provide 1.10 g (71%) of ethyl(6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamateas a white solid.

Example 3-36-3: Preparation of Ethyl(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)carbamate

To a stirred solution of ethyl(6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate(0.300 g, 0.51 mmol), phenylboronic acid (0.093 g, 0.76 mmol), andsodium carbonate (0.108 g, 1.20 mmol) in 1,4-dioxane (8 mL) and water (3mL) was added (1,1′-bis(diphenylphosphino)ferrocene)palladium(II)dichloride (0.080 g, 0.11 mmol). The mixture was heated to 60° C. undera nitrogen atmosphere. After 4 h, the reaction mixture was allowed tocool to room temperature and was filtered through Celite. The filtratewas diluted with water (40 mL) and extracted with ethyl acetate (3×20mL). The combined organic phases were washed with brine (2×20 mL), driedover sodium sulfate, filtered, and concentrated. Chromatographicpurification of the residue (silica gel, 2% methanol in dichloromethaneelute) afforded 0.100 g (40%) of ethyl(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)carbamateas a white solid.

Example 3-36-4: Preparation of3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-phenyl-3H-imidazo[4,5-b]pyridin-2-amine

To a stirred solution of ethyl(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)carbamate(0.090 g, 0.17 mmol) in ethylene glycol (10 mL) and water (10 mL) wasadded potassium hydroxide (1.00 g, 17.82 mmol). The mixture was heatedto 100° C. After 48 h, the mixture was allowed to cool to roomtemperature and was diluted with water (30 mL). The mixture wasextracted with dichloromethane (3×10 mL). The combined organic phaseswere dried over sodium sulfate, filtered, and concentrated. The residuewas purified by prep-HPLC to afford 0.027 g (34%) of the product as ayellow solid: ¹H NMR (500 MHz, CDCl₃) δ 8.36 (s, 1H), 8.21 (s, 1H), 7.87(s, 1H), 7.70-7.68 (m, 3H), 7.50 (s, 2H), 7.40 (s, 1H), 6.90-6.77 (m,4H), 5.31 (s, 2H), 5.05 (s, 2H), 4.77 (s, 2H), 3.95 (s, 3H), 3.81 (s,3H) ppm; (M+1)=468.

Example 3-37: Synthesis of Additional Compounds from Ethyl(6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate

The following compounds were prepared from ethyl(6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamateusing a modification of the procedure described in Example 3-36-3 byemploying the appropriate boronic acid/boronate ester coupling partner.For these compounds, the reactions were conducted under microwaveirradiation (140° C. for 1.5 h). Under these conditions, both the Suzukicoupling and hydrolysis of the carbamate were accomplished in one step:

Example 3-37-1:6-(4-fluorophenyl)-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amine

¹H NMR (500 MHz, DMSO-d₆) δ 8.21 (d, J=2.0 Hz, 1H), 8.14 (d, J=1.5 Hz,1H), 7.75-7.69 (m, 3H), 7.66 (d, J=2.0 Hz, 1H), 7.30-7.26 (m, 2H), 7.12(d, J=2.0 Hz, 1H), 7.00-6.98 (m, 3H), 6.83 (d, J=8.5 Hz, 1H), 6.73 (dd,J=8.0 Hz & 1.5 Hz, 1H), 5.23 (s, 2H), 4.96 (s, 2H), 3.84 (s, 3H), 3.72(s, 3H) ppm; (M+1)=486.

Example 3-37-2:3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-methyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-2-amine(RA09936946)

¹H NMR (500 MHz, CDCl₃) δ 8.55 (d, J=1.5 Hz, 1H), 8.18 (d, J=2.5 Hz,1H), 8.03 (d, J=2.0 Hz, 1H), 7.66 (dd, J=6.5, 2.0 Hz, 1H), 7.41 (d,J=2.5 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.83-6.81 (m, 1H), 6.77 (dd,J=6.5, 2.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.55 (d, J=2.5 Hz, 1H), 5.26(s, 2H), 5.03 (s, 2H), 4.74 (br s, 2H), 3.98 (s, 3H), 3.93 (s, 3H), 3.77(s, 3H) ppm; (M+1)=472.

Example 3-37-3:3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(pyrimidin-5-yl)-3H-imidazo[4,5-b]pyridin-2-amine(RA09943893)

¹H NMR (500 MHz, DMSO-d₆) δ 9.17-9.15 (m, 3H), 8.29 (d, J=2.0 Hz, 1H),8.20 (d, J=2.0 Hz, 1H), 7.86 (d, J=1.5 Hz, 1H), 7.74 (dd, J=8.5, 2.5 Hz,1H), 7.12 (d, J=1.5 Hz, 1H), 7.08 (s, 2H), 6.99 (d, J=8.0 Hz, 1H), 6.83(d, J=8.5 Hz, 1H), 6.74-6.72 (m, 1H), 5.25 (s, 2H), 4.97 (s, 2H), 3.84(s, 3H), 3.72 (s, 3H) ppm; (M+1)=470.

Example 3-37-4:3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

¹H NMR (500 MHz, CDCl₃) δ 8.21 (d, J=2.5 Hz, 1H), 8.18 (d, J=1.5 Hz,1H), 7.69 (dd, J=6.5, 2.0 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 6.92-6.88 (m,2H), 6.81 (dd, J=6.0, 2.0 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 5.29 (s, 2H),5.06 (s, 2H), 4.77 (br s, 2H), 3.95 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H),2.28 (s, 3H), 2.27 (s, 3H) ppm; (M+1)=500.

Example 3-37-5:3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

¹H NMR (500 MHz, DMSO-d₆) δ 8.60-8.59 (m, 2H), 8.33 (d, J=1.5 Hz, 1H),8.20 (d, J=2.0 Hz, 1H), 7.83 (d, J=1.5 Hz, 1H), 7.75-7.73 (m, 3H), 7.12(d, J=2.0 Hz, 1H), 7.06 (s, 2H), 6.99 (d, J=8.0 Hz, 1H), 6.82 (d, J=8.5Hz, 1H), 6.73 (dd, J=8.5, 1.5 Hz, 1H), 5.24 (s, 2H), 4.96 (s, 2H), 3.84(s, 3H), 3.71 (s, 3H) ppm; (M+1)=469.

Example 3-37-6:3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-2-amine

¹H NMR (500 MHz, DMSO-d₆) δ 8.90 (d, J=2.0 Hz, 1H), 8.55-8.54 (m, 1H),8.21-8.20 (m, 2H), 8.09 (d, J=2.0 Hz, 1H), 7.75-7.72 (m, 2H), 7.47-7.42(m, 1H), 7.11 (d, J=1.5 Hz, 1H), 7.03-6.98 (m, 3H), 6.82 (d, J=8.5 Hz,1H), 6.74-6.72 (m, 1H), 5.24 (s, 2H), 4.96 (s, 2H), 3.83 (s, 3H), 3.71(s, 3H); (M+1)=469.

Example 3-38: Synthesis of3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-2-amine

To a stirred solution of ethyl(6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate(0.250 g, 0.42 mmol), 2-(tributylstannyl)pyridine (0.235 g, 0.63 mmol),copper(I) iodide (0.040 g, 0.21 mmol) and triethylamine (0.130 g, 1.26mmol) in N,N-dimethylformamide (5 mL) was addedbis(triphenylphosphine)palladium(II) dichloride (0.018 g, 0.042 mmol).The mixture was irradiated in a microwave reactor at 140° C. After 1.5h, the mixture was allowed to cool to room temperature and was filteredthrough Celite. The filtrate was concentrated. The residue was purifiedby prep-HPLC to afford 0.025 g (13%) of the product as a white solid: ¹HNMR (500 MHz, DMSO-d₆) δ 8.64 (d, J=4.0 Hz, 1H), 8.62 (d, J=2.0 Hz, 1H),8.20 (d, J=2.5 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.97 (d, J=7.5 Hz, 1H),7.84-7.76 (m, 1H), 7.74-7.72 (m, 1H), 7.32-7.29 (m, 1H), 7.12 (d, J=6.0Hz, 1H), 7.00-6.77 (m, 3H), 6.82 (d, J=8.5 Hz, 1H), 6.83-6.74 (m, 1H),5.24 (s, 2H), 4.96 (s, 2H), 3.83 (s, 3H), 3.70 (s, 3H) ppm; (M+1)=469.

Example 3-39: Synthesis of3-(3-methoxy-4-((4-(perfluoroethyl)benzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amineExample 3-39-1: Preparation of 4-(perfluoroethyl)benzyl4-methylbenzenesulfonate

To a stirred solution of (4-(perfluoroethyl)phenyl)methanol (0.60 g,2.65 mmol) and triethylamine (0.53 g, 5.30 mmol) in dichloromethane (30mL) was added p-toluenesulfonyl chloride (1.00 g, 5.30 mmol). Theresulting mixture was allowed to stir at room temperature. After 2 h,the mixture was concentrated. Chromatographic purification of theresidue (silica gel, 10% ethyl acetate in petroleum ether elute)afforded 0.400 g (40%) of 4-(perfluoroethyl)benzyl4-methylbenzenesulfonate as a yellow oil.

Example 3-39-2: Preparation of Ethyl(6-iodo-3-(3-methoxy-4-((4-(perfluoroethyl)benzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate

To a stirred solution of ethyl(3-(4-hydroxy-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5-b]pyridin-2-yl)carbamate(Example 3-36-1) (0.24 g, 0.52 mmol) in tetrahydrofuran (20 mL) wasadded 5M aqueous sodium hydroxide solution (0.2 mLs, 1.00 mmol). Theresulting mixture was allowed to stir at room temperature. After 2 h,the mixture was concentrated, and the residue was dissolved inN,N-dimethylformamide (10 mL). The mixture was treated with4-(perfluoroethyl)benzyl 4-methylbenzenesulfonate (0.40 g, 1.04 mmol),and the mixture was warmed to 80° C. After 3 h, the mixture was allowedto cool to room temperature and was diluted with water (20 mL). Themixture was extracted with ethyl acetate (3×40 mL), and the combinedorganic phases were dried over sodium sulfate, filtered, andconcentrated to provide 0.090 g of ethyl(6-iodo-3-(3-methoxy-4-((4-(perfluoroethyl)benzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamateas a brown solid.

Example 3-39-3: Preparation of3-(3-methoxy-4-((4-(perfluoroethyl)benzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

To a stirred solution of ethyl(6-iodo-3-(3-methoxy-4-((4-(perfluoroethyl)benzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate(0.090 g, 0.13 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.054 g, 0.26 mmol) in N,N-dimethylformamide (3 mL) and 2M aqueoussodium carbonate solution (150 μL) was added(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.050 g,0.06 mmol). The resulting mixture was heated to 80° C. under a nitrogenatmosphere. After 4 h, the mixture was allowed to cool to roomtemperature and was filtered through Celite. The filtrate was dilutedwith water (10 mL) and extracted with ethyl acetate (3×20 mL). Thecombined organic phases were dried over sodium sulfate, filtered, andconcentrated. The residue was purified by prep-HPLC to afford 0.010 g(14%) of the product as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.10(s, 2H), 7.84 (s, 1H), 7.72-7.70 (m, 2H), 7.66-7.64 (m, 2H), 7.58 (d,J=1.6 Hz, 1H), 7.12 (d, J=1.6 Hz, 1H), 6.95-6.89 (m, s3H), 6.72 (d,J=6.8 Hz, 1H), 5.19 (s, 2H), 5.15 (s, 2H), 3.85 (s, 3H), 3.73 (s, 3H)ppm; (M+1)=559.

Example 3-40: Synthesis of Additional Compounds from Ethyl(3-(4-hydroxy-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5-b]pyridin-2-yl)carbamate

The following compounds were prepared from ethyl(3-(4-hydroxy-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5-b]pyridin-2-yl)carbamateusing the procedures described in Example 3-39-2 and Example 3-39-3 byemploying the appropriate alkylating agent:

Example 3-40-1:3-(3-methoxy-4-((4-(trifluoromethoxy)benzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine(RA10502607)

¹H NMR (500 MHz, DMSO-d₆) δ 8.11 (s, 2H), 7.85 (s, 1H), 7.58 (d, J=2.5Hz, 1H), 7.54-7.53 (m, 2H), 7.37 (d, J=8.0 Hz, 2H), 7.12 (s, 1H), 6.94(d, J=8.0 Hz, 1H), 6.91-6.89 (m, 2H), 6.72 (d, J=7.5 Hz, 1H), 5.19 (s,2H), 5.05 (s, 2H), 3.86 (s, 3H), 3.73 (s, 3H) ppm; (M+1)=525.

Example 3-40-2:3-(3-methoxy-4-((4-((trifluoromethyl)thio)benzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

¹H NMR (400 MHz, CDCl₃) δ 8.26 (d, J=1.6 Hz, 1H), 7.77 (s, 1H), 7.71 (d,J=1.6 Hz, 1H), 7.67-7.64 (m, 3H), 7.49 (d, J=8.4 Hz, 2H), 6.87 (d, J=1.6Hz, 1H), 6.83-6.78 (m, 2H), 5.27 (s, 2H), 5.15 (s, 2H), 3.98 (s, 3H),3.82 (s, 3H) ppm (note: NH₂ portions not observed); (M+1)=541.

Example 3-40-3:3-(4-((6-isopropylpyridin-3-yl)methoxy)-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

¹H NMR (400 MHz, CDCl₃) δ 8.58 (d, J=2.0 Hz, 1H), 8.26 (d, J=1.6 Hz,1H), 7.78 (s, 1H), 7.72-7.70 (m, 2H), 7.64 (s, 1H), 7.21 (d, J=8.0 Hz,1H), 6.89-6.84 (m, 2H), 6.79 (dd, J=6.4, 1.6 Hz, 1H), 5.27 (s, 2H), 5.09(m, 4H), 3.98 (s, 3H), 3.80 (s, 3H), 3.10-3.06 (m, 1H), 1.32 (d, J=6.8Hz, 6H) ppm; (M+1)=484.

Example 3-40-4:3-(3-methoxy-4-((4-(2,2,2-trifluoroethyl)benzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.96 (s, 2H), 8.48 (s, 1H), 8.26 (s, 1H),7.97 (s, 1H), 7.86 (s, 1H), 7.42-7.40 (m, 2H), 7.36-7.34 (m, 2H), 7.18(s, 1H), 6.98-6.96 (m, 1H), 6.83-6.81 (m, 1H), 5.30 (s, 2H), 5.04 (s,2H), 3.88 (s, 3H), 3.75 (s, 3H), 3.66 (q, J 9.6 Hz, 2H) ppm; (M+1)=523.

Example 3-40-5:3-(3-methoxy-4-((2-(trifluoromethyl)thiazol-4-yl)methoxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.16 (s, 1H), 8.11 (s, 2H), 7.85 (s, 1H),7.59 (s, 1H), 7.13 (s, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.92 (s, 2H), 6.75(d, J=8.4 Hz, 1H), 5.20-5.18 (m, 4H), 3.86 (s, 3H), 3.72 (s, 3H) ppm;(M+1)=516.

Example 3-41: Synthesis of6-(cyclohexylethynyl)-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amineExample 3-41-1: Preparation of6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amine

To a stirred solution of ethyl(6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate(Example 3-36-2) (0.42 g, 0.71 mmol) in ethylene glycol (6 mL) and water(1 mL) was added potassium hydroxide (0.197 g, 3.51 mmol). The resultingmixture was heated to 100° C. After 12 h, the mixture was allowed tocool to room temperature and was diluted with brine (40 mL). The mixturewas extracted with ethyl acetate (3×40 mL). The combined organic phaseswere dried over sodium sulfate, filtered, and concentrated.Chromatographic purification of the residue (silica gel, 3% methanol indichloromethane elute) afforded 0.206 g (56%) of6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amineas a yellow solid.

Example 3-41-2: Preparation of6-(cyclohexylethynyl)-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amine

To a stirred suspension of6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amine(0.14 g, 0.27 mmol), ethylnylcyclohexane (0.044 g, 0.41 mmol) inpiperidine (3 mL) was added bis(triphenylphosphine)palladium(II)dichloride (0.038 g, 0.054 mmol) and copper(I) iodide (0.021 g, 0.11mmol). The mixture was irradiated in a microwave reactor at 60° C. After30 min, the reaction mixture was allowed to cool to room temperature andwas filtered through Celite. The filtrate was concentrated, and theresidue was purified by prep-HPLC to provide 0.032 g (23%) of theproduct as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 8.20 (s, 1H), 7.91(s, 1H), 7.74 (dd, J=8.5, 1.5 Hz, 1H), 7.42-7.32 (m, 1H), 7.07-6.97 (m,4H), 6.83 (d, J=8.5 Hz, 1H), 6.71 (d, J=7.5 Hz, 1H), 5.20 (s, 2H), 4.96(s, 2H), 3.84 (s, 3H), 3.69 (s, 3H), 2.65-2.58 (m, 1H), 1.88-1.78 (m,2H), 1.75-1.62 (m, 2H), 1.50-1.46 (m, 3H), 1.35-1.32 (m, 3H) ppm;(M+1)=498.

Example 3-42: Synthesis of4-(2-amino-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)but-3-yn-1-ol

This compound was prepared from6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amineand but-3-yn-1-ol using the procedure described in Example 3-41-2: ¹HNMR (500 MHz, DMSO-d₆) δ 8.21 (s, 1H), 7.93 (s, 1H), 7.74 (dd, J=8.5,2.0 Hz, 1H), 7.41 (s, 1H), 7.08-6.97 (m, 4H), 6.83 (d, J=8.5 Hz, 1H),6.71 (d, J=8.0 Hz, 1H), 5.20 (s, 2H), 4.96 (s, 2H), 4.91 (t, J=5.5 Hz,1H), 3.84 (s, 3H), 3.69 (s, 3H), 3.61-3.57 (m, 2H), 2.56 (t, J=6.5 Hz,2H) ppm; (M+1)=460.

Example 3-43: Synthesis of3-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amineExample 3-43-1: Preparation ofcyclopropyl(6-methoxypyridin-3-yl)methanol

To a stirred −78° C. solution of 5-bromo-2-methoxypyridine (3.70 g,19.79 mmol) in tetrahydrofuran (10 mL) was added 2.6 M n-butyllithiumsolution in hexane (8.4 mL, 21.84 mmol). The mixture was allowed to stirat −78° C. for 30 min, and then cyclopropanecarboxaldehye (1.70 g, 23.74mmol) was added in one portion. The cooling bath was removed, and themixture was allowed to warm to room temperature. After 2 h, the mixturewas quenched by the addition of saturated aqueous ammonium chloridesolution (100 mL). The resulting mixture was extracted with ethylacetate (3×100 mL). The combined organic phases were dried over sodiumsulfate, filtered, and concentrated. Chromatographic purification of theresidue (silica gel, 20% ethyl acetate in petroleum ether elute)afforded 2.90 g (80%) of cyclopropyl(6-methoxypyridin-3-yl)methanol as ayellow oil.

Example 3-43-2: Preparation of4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzonitrile

To a stirred 0° C. solution ofcyclopropyl(6-methoxypyridin-3-yl)methanol (3.80 g, 21.20 mmol),4-hydroxy-3-methoxybenzonitrile (1.60 g, 10.73 mmol), andtriphenylphosphine (5.60 g, 21.35 mmol) in tetrahydrofuran (10 mL) wasadded diethyl azodicarboxylate (3.70 g, 21.25 mmol) dropwise. Theresulting mixture was allowed to warm to room temperature. After 2 h,the mixture was concentrated. Chromatographic purification of theresidue (silica gel, 10% ethyl acetate in petroleum ether elute)afforded 2.70 g (80%) of4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzonitrile as alight yellow oil.

Example 3-43-3: Preparation of(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxyphenyl)methanamine

To a stirred 0° C. solution of4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzonitrile(2.50 g, 8.06 mmol) in ethanol (20 mL) was added cobalt(II) chloridehexahydrate (2.20 g, 9.25 mmol) in small portions. The resulting mixturewas allowed to stir at 0° C. After 30 min, the mixture was treated withsodium borohydride (1.80 g, 47.58 mmol) added in small portions. Themixture was allowed to warm to room temperature. After 30 min, themixture was filtered through Celite, and the filtercake was washed withethanol (20 mL). The filtrate was concentrated to provide 2.50 g (99%)of(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxyphenyl)methanamineas a colorless oil.

Example 3-43-4: Preparation ofN-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5-iodo-3-nitropyridin-2-amine

To a stirred solution of(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxyphenyl)methanamine(2.50 g, 7.95 mmol) and potassium carbonate (1.41 g, 10.20 mmol) inacetonitrile (10 mL) was added 2-chloro-5-iodo-3-nitropyridine (2.90 g,10.20 mmol). The resulting mixture was heated to 80° C. After 2 h, themixture was filtered, and the filtrate was concentrated. Chromatographicpurification of the residue (silica gel, 20% ethyl acetate in petroleumether elute) afforded 2.60 g (58%) ofN-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5-iodo-3-nitropyridin-2-amineas a yellow oil.

Example 3-43-5: Preparation ofN-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5-(1-methyl-1H-pyrazol-4-yl)-3-nitropyridin-2-amine

To a stirred solution ofN-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5-iodo-3-nitropyridin-2-amine(2.20 g, 3.91 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.896 g, 4.30 mmol), and potassium carbonate (1.10 g, 7.95 mmol) intoluene (10 mL) and water (1 mL) was added(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.143 g,0.20 mmol). The resulting mixture was heated to 100° C. and stirredunder a nitrogen atmosphere. After 16 h, the mixture was allowed to coolto room temperature and was diluted with water (15 mL). The mixture wasextracted with ethyl acetate (2×60 mL). The combined organic phases weredried over sodium sulfate, filtered, and concentrated. Chromatographicpurification of the residue (silica gel, 33% ethyl acetate in petroleumether elute) afforded 1.10 g (55%) ofN-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5-(1-methyl-1H-pyrazol-4-yl)-3-nitropyridin-2-amineas a light brown solid.

Example 3-43-6: Preparation ofN²-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridine-2,3-diamine

To a stirred solution ofN-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5-(1-methyl-1H-pyrazol-4-yl)-3-nitropyridin-2-amine(1.10 g, 2.13 mmol) and ammonium chloride (0.564 g, 10.54 mmol) inethanol (8 mL) and water (2 mL) was added iron powder (0.596 g, 10.67mmol). The mixture was heated to 80° C. After 2 h, the mixture wasallowed to cool to room temperature and was filtered through Celite. Thefiltrate was concentrated. Chromatographic purification of the residue(neutral alumina, 2% methanol in dichloromethane elute) afforded 0.984 g(95%) ofN²-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridine-2,3-diamineas a brown solid.

Example 3-43-7: Preparation of Ethyl(3-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate

To a stirred solution ofN²-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridine-2,3-diamine(0.55 g, 1.13 mmol) in tetrahydrofuran (5 mL) was added triethylamine(0.799 g, 7.90 mmol). The resulting mixture was allowed to stir at roomtemperature. After 15 min, the mixture was treated with ethylcarbonisothiocyanatidate (0.444 g, 3.39 mmol), and the resulting mixturewas allowed to stir at room temperature. After 30 min, the mixture wasfiltered, and the filtrate was concentrated. The residue was dissolvedin tetrahydrofuran (5 mL) and was treated with triethylamine (0.799 g,7.90 mmol) and benzenesulfonyl chloride (0.259 g, 1.43 mmol). Theresulting mixture was allowed to stir at room temperature. After 16 h,the mixture was concentrated. Chromatographic purification of theresidue (neutral alumina, 50% ethyl acetate in petroleum ether elute)afforded 0.45 g (68%) of ethyl(3-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamateas a brown oil.

Example 3-43-8: Preparation of3-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

To a stirred solution of ethyl(3-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate(0.44 g, 0.75 mmol) in n-butanol (4 mL) and water (4 mL) was addedpotassium hydroxide (0.42 g, 7.49 mmol). The mixture was heated to 130°C. After 16 h, the mixture was allowed to cool to room temperature andwas diluted with water (15 mL). The mixture was extracted with ethylacetate (2×60 mL). The combined organic phases were dried over sodiumsulfate, filtered, and concentrated. The residue was purified viaprep-HPLC to provide 0.058 g (15%) of the product as a white solid: ¹HNMR (500 MHz, CDCl₃) δ 8.24 (d, J=1.5 Hz, 1H), 8.09 (d, J=3.0 Hz, 1H),7.78 (s, 1H), 7.70-7.68 (m, 2H), 7.64 (s, 1H), 6.78-6.23 (m, 4H), 5.21(s, 2H), 4.85 (s, 2H), 4.50 (d, J=8.5 Hz, 1H), 3.98 (s, 3H), 3.93 (s,3H), 3.79 (s, 3H), 1.45-1.40 (m, 1H), 0.75-0.70 (m, 1H), 0.61-0.50 (m,2H), 0.38-0.34 (m, 1H) ppm; (M+1)=512.

Example 3-44: Synthesis of3-(3-methoxy-4-((3-methoxy-5,6,7,8-tetrahydroisoquinolin-8-yl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amineExample 3-44-1: Preparation of3-methoxy-5,6,7,8-tetrahydroisoquinolin-8-ol

To a stirred 0° C. solution of3-methoxy-6,7-dihydroisoquinolin-8(5H)-one (1.90 g, 10.72 mmol) inmethanol (30 mL) was added sodium borohydride (1.10 g, 29.08 mmol) insmall portions. The resulting mixture was allowed to warm to roomtemperature. After 2 h, the mixture was quenched with water (20 mL) andwas extracted with ethyl acetate (3×100 mL). The combined organic phaseswere dried over sodium sulfate, filtered, and concentrated.Chromatographic purification of the residue (silica gel, 50% ethylacetate in petroleum ether elute) afforded 1.60 g (85%) of3-methoxy-5,6,7,8-tetrahydroisoquinolin-8-ol as a light yellow solid.

Example 3-44-2: Preparation of3-(3-methoxy-4-((3-methoxy-5,6,7,8-tetrahydroisoquinolin-8-yl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

This compound was prepared from3-methoxy-5,6,7,8-tetrahydroisoquinolin-8-ol using the proceduresoutlined in Example 3-43-2 through Example 3-43-8: ¹H NMR (400 MHz,CDCl₃) δ 8.25 (d, J=1.6 Hz, 1H), 8.12 (s, 1H), 7.77 (s, 1H), 7.70 (d,J=2.0 Hz, 1H), 7.63 (s, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.84 (d, J=1.6 Hz,1H), 6.79 (dd, J=8.4, 1.6 Hz, 1H), 6.50 (s, 1H), 5.27-5.24 (m, 3H), 5.03(s, 2H), 3.97 (s, 3H), 3.89 (s, 3H), 3.76 (s, 3H), 2.87-2.81 (m, 1H),2.72-2.65 (m, 1H), 2.19-1.73 (m, 4H) ppm; (M+1)=512

Example 3-45: Synthesis of1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amineExample 3-45-1: Preparation of1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-one

To a stirred suspension of 1-(4-hydroxy-3-methoxyphenyl)ethan-1-one(3.96 g, 23.82 mmol) and potassium carbonate (13.17 g, 95.29 mmol) inacetonitrile (75 mL) was added 5-(chloromethyl)-2-methoxypyridinehydrochloride (4.85 g, 25.01 mmol). After 2 h, the mixture was dilutedwith water (150 mL) and extracted with dichloromethane (3×100 mL). Thecombined organic phases were dried over magnesium sulfate, filtered, andconcentrated to provide a yellow oil. Trituration of the crude materialwith hexanes afforded 5.48 g (85%) of1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-one as awhite solid.

Example 3-45-2: Preparation of1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-one Oxime

To a stirred suspension of1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-one (5.48g, 19.07 mmol) and potassium carbonate (10.54 g, 76.29 mmol) in methanol(100 mL) and water (10 mL) was added hydroxylamine sulfate (4.70 g,28.61 mmol). The resulting mixture was heated to reflux. After 64 h, themixture was allowed to cool to room temperature and was diluted withwater (250 mL). The resulting suspension was filtered, and thefiltercake was washed with water (50 mL) and dried to provide 5.55 g(96%) of1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-one oximeas a white solid.

Example 3-45-3: Preparation of1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-amine

To a stirred solution of1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-one oxime(5.55 g, 18.36 mmol) in acetic acid (40 mL) was added zinc dust (6.00 g,91.79 mmol). The resulting mixture was heated to 65° C. After 1 h, themixture was allowed to cool to room temperature and was filtered throughCelite. The filtercake was washed with methanol (100 mL). The filtratewas concentrated, and the residue dissolved in 5N ammonium hydroxidesolution (75 mL). The mixture was extracted with chloroform (2×50 mL).The combined organic phases were dried over magnesium sulfate, filtered,and concentrated to provide 4.56 g (86%) of1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-amine as ayellow oil.

Example 3-45-4: Preparation of4-iodo-N-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)-2-nitroaniline

To a stirred solution of1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-amine(1.93 g, 6.68 mmol) and potassium carbonate (3.70 g, 26.75 mmol) inacetonitrile (75 mL) was added 1-fluoro-4-iodo-2-nitrobenzene (2.14 g,8.02 mmol). The mixture was heated to reflux. After 16 h, the orangemixture was allowed to cool to room temperature and was diluted withwater (150 mL). The mixture was extracted with dichloromethane (3×75mL), and the combined organic phases were dried over magnesium sulfate,filtered, and concentrated to provide 3.82 g of an orange solid.Trituration of the crude material with hexanes afforded 3.17 g (89%) of4-iodo-N-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)-2-nitroanilineas a bright orange solid.

Example 3-45-5: Preparation of4-iodo-N1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)benzene-1,2-diamine

To a stirred suspension of4-iodo-N-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)-2-nitroaniline(3.17 g, 5.92 mmol) and ammonium chloride (2.53 g, 47.37 mmol) intetrahydrofuran (50 mL)/methanol (20 mL)/water (10 mL) was addediron(II) sulfate heptahydrate (5.76 g, 20.73 mmol) and zinc dust (1.35g, 20.73 mmol). The resulting mixture was heated to reflux. After 1 h,the mixture was allowed to cool to room temperature and was filteredthrough Celite. The filtercake was washed with methanol (50 mL). Thefiltrate was concentrated, and the residue was diluted with 3N ammoniumhydroxide solution (100 mL). The basic mixture was extracted withchloroform (3×50 mL), and the combined organic phases were dried overmagnesium sulfate, filtered, and concentrated to provide 2.02 g (68%) of4-iodo-N¹-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)benzene-1,2-diamineas a brown solid.

Example 3-45-6: Preparation of5-iodo-1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazol-2-amine

To a stirred solution of4-iodo-N¹-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)benzene-1,2-diamine(2.02 g, 4.00 mmol) in dichloromethane (20 mL)/methanol (10 mL) wasadded cyanogen bromide solution (5.0M in acetonitrile, 4.0 mL, 20.00mmol). The resulting dark brown solution was allowed to stir at roomtemperature. After 17 h, the mixture was diluted with 1N sodiumhydroxide solution (20 mL), and the basic mixture was allowed to stir.After 30 min, the phases were separated, and the aqueous phase wasextracted with chloroform (30 mL). The combined organic phases weredried over magnesium sulfate, filtered, and concentrated to provide 3.36g of a brown oil. Chromatographic purification of the residue(CombiFlash, 120 g SiO₂ gold column, 1-5% methanol in dichloromethaneelute) provided a brown semi-solid. Trituration of this material with1:1 diethyl ether/dichloromethane afforded 0.801 g (38%) of5-iodo-1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazol-2-amineas a tan solid.

Example 3-45-7: Preparation of1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine

To stirred mixture of5-iodo-1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazol-2-amine(0.267 g, 0.50 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.138 g, 0.63 mmol), tricyclohexylphosphine (0.014 g, 0.050 mmol),potassium phosphate tribasic (0.381 g, 1.76 mmol) in 1,4-dioxane (3 mL)and water (1 mL) was added palladium(II) acetate (0.005 g, 0.025 mmol).The mixture was heated to 125° C. in a microwave reactor. After 30 min,additional portions of catalyst (0.005 g) and ligand (0.014 g) wereadded, and the mixture was reheated in a microwave reactor to 150° C.After 60 min of reaction time, the crude mixture was transferred to a 20mL microwave reaction vial and was treated with an additional portionsof boronate ester (0.050 g), catalyst (0.005 g), and ligand (0.014 g).The mixture was diluted with additional 1,4-dioxane (8 mL) and water (4mL). The mixture was heated to 150° C. in a microwave reactor. After atotal of 105 min, the reaction was complete. The mixture was dilutedwith water (30 mL) and extracted with dichloromethane (3×25 mL). Thecombined organic phases were dried over magnesium sulfate, filtered, andconcentrated to provide 419 mgs of a brown oil. Chromatographicpurification (CombiFlash, 12 g SiO₂ gold column, 1-5% 2M ammonia inmethanol/dichloromethane elute) provided 109 mgs of an impure tan solid.A second chromatographic purification (CombiFlash, 12 g SiO₂ goldcolumn, 1-5% 2M ammonia in methanol/dichloromethane elute) afforded0.063 g (26%) of the product as as a yellow solid: ¹H NMR (400 MHz,CDCl₃) δ 8.22-8.16 (m, 1H), 7.75 (d, J=0.8 Hz, 1H), 7.68 (dd, J=8.5, 2.4Hz, 1H), 7.58 (d, J=0.8 Hz, 1H), 7.53 (d, J=1.5 Hz, 1H), 7.20-7.16 (m,1H), 7.11-7.06 (m, 1H), 6.96-6.87 (m, 2H), 6.80-6.73 (m, 2H), 5.55 (q,J=7.1 Hz, 1H), 5.05 (s, 2H), 4.33 (br s, 2H), 3.95 (s, 3H), 3.94 (s,3H), 3.76 (s, 3H), 1.87 (d, J=7.1 Hz, 3H) ppm; (M+1)=485.

Example 3-46: Synthesis of5-(4-fluorophenyl)-1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazol-2-amine

To a stirred solution of5-iodo-1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazol-2-amine(Example 3-45-6) (0.195 g, 0.37 mmol), 4-fluorophenylboronic acid (0.064g, 0.46 mmol), and potassium phosphate tribasic (0.413 g, 1.91 mmol) intetrahydrofuran (5 mL)/water (4 mL) was added 2^(nd) generation XPhosprecatalyst (0.015 g, 0.018 mmol). The yellow solution was degassedunder vacuum/backfilled with nitrogen (×3). The mixture was heated to60° C. After 90 min, the mixture was treated with an additional portionof boronic acid (0.030 g) and precatalyst (0.014 g), and the temperaturewas increased to 75° C. After a total reaction time of 150 min, thebrown mixture was allowed to cool to room temperature and was dilutedwith water (30 mL). The mixture was extracted with dichloromethane (3×25mL). The combined organic phases were dried over magnesium sulfate,filtered, and concentrated to provide 0.282 g of a brown oil.Chromatographic purification (CombiFlash, 12 g SiO₂ gold column, 1-5% 2Mammonia in methanol/dichloromethane elute) afforded 0.142 g (78%) of theproduct as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 8.20 (dd, J=2.4,0.8 Hz, 1H), 7.68 (dd, J=8.4, 2.5 Hz, 1H), 7.62-7.52 (m, 3H), 7.23 (dd,J=8.4, 1.7 Hz, 1H), 7.17-7.06 (m, 3H), 6.96-6.88 (m, 2H), 6.81-6.79 (m,1H), 6.78-6.74 (m, 1H), 5.58 (q, J=7.0 Hz, 1H), 5.05 (s, 2H), 4.49 (s,2H), 3.93 (s, 3H), 3.76 (s, 3H), 1.88 (d, J=7.0 Hz, 3H) ppm; (M+1)=499.

Example 3-47: Synthesis of5-(4-fluorophenyl)-1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazoleExample 3-47-1: Preparation of5-iodo-1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole

To stirred solution of4-iodo-N1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)benzene-1,2-diamine[prepared from 5-(chloromethyl)-2-(trifluoromethyl)pyridine using theprocedures described in Example 3-45-1 through Example 3-45-5] (1.04 g,1.91 mmol) in ethanol (30 mL) was added triethyl orthoformate (1.0 mL,5.89 mmol) and p-toluenesulfonic acid monohydrate (0.025 g, 0.13 mmol).The yellow solution was heated to reflux. After 30 min, the mixture wasallowed to cool to room temperature and was concentrated to provide ayellow oil. Chromatographic purification (CombiFlash, 24 g SiO₂ goldcolumn, 1-5% methanol/dichloromethane elute) afforded 0.803 g (76%) of5-iodo-1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazoleas a yellow solid.

Example 3-47-2 Preparation of5-(4-fluorophenyl)-1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole

To a stirred solution of5-iodo-1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole(0.248 g, 0.45 mmol), (4-fluorophenyl)boronic acid (0.088 g, 0.63 mmol),and potassium phosphate tribasic (0.485 g, 2.24 mmol) in tetrahydrofuran(7 mL)/water (5 mL) was added 2^(nd) generation XPhos precatalyst (0.024g, 0.031 mmol). The yellow solution was degassed under vacuum/backfilledwith nitrogen (×3). The mixture was heated to 75° C. After 45 min, thebrown reaction mixture was allowed to cool to room temperature and wasdiluted with water (30 mL). The mixture was extracted withdichloromethane (2×25 mL). The combined organic phases were dried overmagnesium sulfate, filtered, and concentrated to provide 0.271 g of abrown oil. Chromatographic purification (CombiFlash, 12 g SiO₂ goldcolumn, 1-5% methanol/dichloromethane elute) afforded 0.200 g (86%) ofthe product as an off-white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.78 (d,J=2.0 Hz, 1H), 8.08 (s, 1H), 7.99-7.94 (m, 2H), 7.70 (dd, J=8.1, 0.8 Hz,1H), 7.61-7.52 (m, 2H), 7.40 (dd, J=8.4, 1.7 Hz, 1H), 7.27-7.23 (m, 1H),7.16-7.09 (m, 2H), 6.88-6.84 (m, 1H), 6.80-6.76 (m, 1H), 6.75-6.73 (m,1H), 5.60 (q, J=7.0 Hz, 1H), 5.20 (s, 2H), 3.80 (s, 3H), 2.01 (d, J=7.0Hz, 3H) ppm; (M+1)=522.

Example 3-48: Synthesis of Additional Compounds from5-iodo-1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole

The following compound was prepared from5-iodo-1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazoleusing the procedure described in Example 3-47-2 by employing theappropriate boronate ester coupling partner.

Example 3-48-1:1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazole

¹H NMR (400 MHz, CDCl₃) δ 8.82-8.75 (m, 1H), 8.04 (s, 1H), 7.99-7.93 (m,1H), 7.89 (dd, J=1.7, 0.7 Hz, 1H), 7.76 (d, J=0.8 Hz, 1H), 7.72-7.68 (m,1H), 7.64-7.57 (m, 1H), 7.34 (dd, J=8.4, 1.6 Hz, 1H), 7.18 (dd, J=8.4,0.7 Hz, 1H), 6.85 (d, J=8.2 Hz, 1H), 6.80-6.70 (m, 2H), 5.57 (q, J=7.0Hz, 1H), 5.20 (s, 2H), 3.95 (s, 3H), 3.79 (s, 3H), 1.99 (d, J=7.0 Hz,3H) ppm; (M+1)=508.

Example 3-48-2:4-(1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazol-5-yl)but-3-yn-1-ol

To a stirred mixture of5-iodo-1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole(0.210 g, 0.38 mmol), 3-butyn-1-ol (0.041 g, 0.57 mmol), copper(I)iodide (0.019 g, 0.10 mmol) in piperidine (4 mL) was addedbis(triphenylphosphine)palladium(II) chloride (0.037 g, 0.053 mmol). Themixture heated to 100° C. in a microwave reactor. After 30 min, thereaction mixture was allowed to cool to room temperature and was dilutedwith 5N ammonium hydroxide solution (30 mL). The mixture was extractedwith dichloromethane (3×25 mL). The combined organic phases were driedover magnesium sulfate, filtered, and concentrated to provide 0.386 g ofa brown solid. Chromatographic purification (CombiFlash, 12 g SiO₂ goldcolumn, 1-5% methanol/dichloromethane elute) afforded 0.157 g (84%) ofthe product as a light yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 8.78 (d,J=2.1 Hz, 1H), 8.04 (s, 1H), 8.00-7.93 (m, 1H), 7.90-7.84 (m, 1H),7.72-7.68 (m, 1H), 7.28-7.23 (m, 1H), 7.13-7.08 (m, 1H), 6.87-6.82 (m,1H), 6.76-6.64 (m, 2H), 5.55 (q, J=7.0 Hz, 1H), 5.19 (s, 2H), 3.83 (t,J=6.2 Hz, 2H), 3.77 (s, 3H), 2.71 (t, J=6.2 Hz, 2H), 2.00-1.92 (m, 4H)ppm; (M+1)=496.

Example 3-49: Synthesis of3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amineExample 3-49-1: Preparation of5-iodo-N-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3-nitropyridin-2-amine

To a stirred solution of1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethanamine[prepared from 1-(chloromethyl)-4-(trifluoromethyl)benzene using theprocedures described in Example 3-45-1 through Example 3-45-3] (2.52 g,7.75 mmol) and N,N-diisopropylethylamine (2.7 mL, 15.18 mmol) inacetonitrile (30 mL) was added 2-chloro-5-iodo-3-nitropyridine (2.39 g,8.13 mmol), The orange solution was heated to reflux. After 15 h, thebrown reaction mixture was allowed to cool to room temperature and wasdiluted with water (60 mL). As the mixture was stirred, a yellowprecipitate formed. The solids were isolated by filtration and washedwith water (50 mL), and dried to provide 4.19 g (94%) of5-iodo-N-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3-nitropyridin-2-amineas a yellow solid.

Example 3-49-2: Preparation of5-iodo-N²-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)pyridine-2,3-diamine

To a stirred mixture of5-iodo-N-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3-nitropyridin-2-amine(4.19 g, 7.31 mmol), and ammonium chloride (3.14 g, 58.47 mmol) intetrahydrofuran (40 mL)/methanol (40 mL)/water (20 mL) was addediron(II) sulfate heptahydrate (7.18 g, 25.58 mmol) and zinc dust (1.69g, 25.58 mmol). The yellow mixture was heated to 60° C. As the mixturewarmed, an olive green color developed. After 5 min, the warm reactionmixture was filtered through Celite with the aid of ethyl acetate (100mL). The filtrate was diluted with 5N ammonium hydroxide solution (30mL), and the phases were separated. The aqueous phase was extracted withethyl acetate (2×50 mL). The combined organic phases were dried overmagnesium sulfate, filtered, and concentrated to provide 3.72 g of abrown oil. Chromatographic purification (CombiFlash, 120 g SiO₂ goldcolumn, 30-60% ethyl acetate/heptane elute) afforded 2.39 g (60%) of5-iodo-N²-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)pyridine-2,3-diamineas an off-white solid.

Example 3-49-3: Preparation of Ethyl(6-iodo-3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate

To stirred solution of5-iodo-N²-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)pyridine-2,3-diamine(2.39 g, 4.40 mmol) and triethylamine (0.92 ml, 6.60 mmol) intetrahydrofuran (30 mL) was added with ethoxycarbonyl isothiocyanate(0.64 ml, 5.28 mmol). After 3 h, the mixture was diluted with brine (100mL) and extracted with ethyl acetate (3×50 mL). The combined organicphases were dried over magnesium sulfate, filtered, and concentrated toprovide 3.16 g of a brown foamy solid. The crude solid was dissolved intetrahydrofuran (30 mL) and was treated with triethylamine (1.53 mL,11.01 mmol) and benzenesulfonyl chloride (1.42 mL, 11.01 mmol). Theyellow mixture was allowed to stir at room temperature. After 63 h, themixture was diluted with water (100 mL) and allowed to stir at roomtemperature. After 2 h, the reaction mixture was extracted withdichloromethane (3×50 mL). The combined organic phases were washed withsaturated potassium carbonate solution (50 mL), dried over magnesiumsulfate, filtered, and concentrated to provide 3.62 g of a brown oil.Chromatographic purification (CombiFlash, 80 g SiO₂ gold column, 10-30%ethyl acetate/heptane elute) provided a tan solid. Trituration of thismaterial with diethyl ether (50 mL) afforded 1.30 g (46%) of ethyl(6-iodo-3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamateas a white solid.

Example 3-49-4: Preparation of6-iodo-3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-amine

To a stirred solution of ethyl(6-iodo-3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate(1.30 g, 2.03 mmol) in ethanol (8 mL)/water (6 mL) was added potassiumphosphate tribasic (1.76 g, 8.12 mmol). The mixture was heated to 160°C. in a microwave reactor. After 1 h, the reaction mixture was dilutedwith water (100 mL), resulting in a precipitate. The solids wereisolated by filtration, washed with water (25 mL), and dried to provide1.02 g (88%) of6-iodo-3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-amineas a white solid.

Example 3-49-5: Preparation of3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

To a stirred mixture of6-iodo-3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-amine(0.253 g, 0.45 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.158 g, 0.76 mmol), potassium phosphate tribasic (0.495 g, 2.29 mmol)in tetrahydrofuran (5 mL)/water (4 mL) was added 2^(nd) generation XPhosprecatalyst (0.032 g, 0.041 mmol). The yellow solution was degassedunder vacuum/backfilled with nitrogen (×3). The mixture heated to 75° C.After 4 h, the mixture was allowed to cool to room temperature and wasdiluted with water (40 mL). The mixture was extracted with ethyl acetate(3×25 mL). The combined organic phases were dried over magnesiumsulfate, filtered, and concentrated to provide 0.320 g of a brown oil.Chromatographic purification (CombiFlash, 12 g SiO₂ gold column, 1-5% 2Mammonia in methanol/dichloromethane elute) afforded 0.178 g (77%) of theproduct as a tan solid: ¹H NMR (400 MHz, CDCl₃) δ 8.25 (d, J=1.9 Hz,1H), 7.77 (d, J=0.8 Hz, 1H), 7.68 (d, J=1.9 Hz, 1H), 7.66-7.62 (m, 3H),7.57-7.53 (m, 2H), 6.96-6.92 (m, 1H), 6.89-6.84 (m, 2H), 6.11 (q, J=7.1Hz, 1H), 5.21 (s, 2H), 4.46 (br s, 2H), 3.98 (s, 3H), 3.80 (s, 3H), 1.87(d, J=7.1 Hz, 3H) ppm; (M+1)=523.

Example 3-49-6 a and Example 3-49-6 b: Chiral Separation of3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

The racemic3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-aminewas subjected to chiral separation using SFC (21×250 mm AS column, 25%methanol/0.5% diethylamine, flow rate 50 g/min) to provide the twoenantiomers. The absolute configuration has not been assigned.

Example 3-50: Synthesis of Additional Compounds from6-iodo-3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-amine

The following compounds were prepared from6-iodo-3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-amineusing the procedure described in Example 3-49-5 by employing theappropriate boronate ester coupling partner.

Example 3-50-1:2-(4-(2-Amino-3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)ethan-1-ol(RA10074277)

¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, J=1.9 Hz, 1H), 7.80 (d, J=0.8 Hz,1H), 7.71 (d, J=0.8 Hz, 1H), 7.68-7.61 (m, 3H), 7.58-7.53 (m, 2H),6.96-6.92 (m, 1H), 6.89-6.84 (m, 2H), 6.11 (q, J=7.1 Hz, 1H), 5.20 (s,2H), 4.44 (br s, 2H), 4.35-4.27 (m, 2H), 4.11-4.02 (m, 2H), 3.80 (s,3H), 1.87 (d, J=7.1 Hz, 3H), 1.68 (s, 1H) ppm; (M+1)=553.

Example 3-50-2:3-(1-(3-Methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-6-(1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine(RA10161874)

¹H NMR (400 MHz, DMSO-d₆) δ 12.90 (s, 1H), 8.17 (d, J=2.0 Hz, 2H),7.96-7.88 (m, 1H), 7.74 (d, J=8.1 Hz, 2H), 7.67-7.59 (m, 3H), 7.23 (d,J=1.3 Hz, 1H), 7.07-6.92 (m, 4H), 5.66 (q, J=7.0 Hz, 1H), 5.16 (s, 2H),3.74 (s, 3H), 2.04 (d, J=7.0 Hz, 3H) ppm; (M+1)=509.

Example 3-51: Synthesis of3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)propyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amineExample 3-51-1: Preparation of3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)benzonitrile

To a stirred solution of (6-(trifluoromethyl)pyridin-3-yl)methanol (2.70g, 15.25 mmol) in dimethylsulfoxide (25 mL) was added 60% sodium hydridedispersion (0.639 g, 15.98 mmol; gas evolution and mild exotherm notedupon addition). After 30 min, the dark brown reaction mixture wastreated with 4-fluoro-3-methoxybenzonitrile (2.24 g, 14.52 mmol) andallowed to stir. 45 min after the addition, the orange-brown mixture wasdiluted with water (150 mL) and extracted with ethyl acetate (3×50 mL).The combined organic phases were washed with brine (50 mL), dried overmagnesium sulfate, filtered, and concentrated to provide 4.50 g of anorange solid. Chromatographic purification (CombiFlash, 120 g SiO₂ goldcolumn, 10-25% ethyl acetate/heptane elute) afforded 1.93 g (43%) of3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)benzonitrile as anoff-white solid.

Example 3-51-2: Preparation of1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)propan-1-one

To a stirred 0° C. solution of3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)benzonitrile (1.69g, 5.48 mmol) in tetrahydrofuran (15 mL) was added ethylmagnesiumbromide solution (1.0 M in tetrahydrofuran, 7.0 mL, 7.00 mmol) followedby copper(I) iodide (0.010 g, 0.055 mmol). The resulting red-brownmixture was allowed to warm to room temperature and stir. After 16 h,the mixture was treated with 1N hydrochloric acid solution (25 mL) andallowed to stir. After 30 min, the mixture was adjusted pH 7 withsaturated potassium carbonate solution (20 mL) and extracted with ethylacetate (3×30 mL). The combined organic phases were dried over magnesiumsulfate, filtered, and concentrated to provide 1.86 g of a brown oil.Chromatographic purification (CombiFlash, 40 g SiO₂ column, 25-50% ethylacetate/heptane elute) afforded 1.44 g (77%)1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)propan-1-oneas an off-white solid.

Example 3-51-3: Preparation of5-iodo-N-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)propyl)-3-nitropyridin-2-amine

This compound was prepared from1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)propan-1-oneusing the procedures described in Example 3-45-2 through Example 3-45-4.

Example 3-51-4: Preparation of5-iodo-N²-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)propyl)pyridine-2,3-diamine

To a stirred suspension of5-iodo-N-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)propyl)-3-nitropyridin-2-amine(1.25 g, 2.12 mmol) in acetic acid (20 mL) was added iron (0.714 g,12.77 mmol). The yellow mixture was heated to 125° C. As the mixture washeated, the yellow color faded and a gray suspension formed. After 10min, the mixture was allowed to cool to room temperature and was dilutedwith ethyl acetate (75 mL). The suspension was filtered through Celitewith the aid of ethyl acetate (50 mL). The filtrate was washed withwater (2×30 mL) and then with concentrated ammonium hydroxide (2×30 mL).The organic phase was dried over magnesium sulfate, filtered, andconcentrated to provide 1.20 g (>100%) of5-iodo-N²-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)propyl)pyridine-2,3-diamineas a brown oil.

Example 3-51-5: Preparation of3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)propyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

This compound was prepared from5-iodo-N²-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)propyl)pyridine-2,3-diamineusing the procedures described in Example 3-49-3 through Example 3-49-5:¹H NMR (400 MHz, CDCl₃) δ 8.79 (s, 1H), 8.25 (d, J=1.7 Hz, 1H), 7.98 (d,J=8.2 Hz, 1H), 7.81-7.59 (m, 4H), 7.01-6.84 (m, 3H), 5.80-5.70 (m, 1H),5.21 (s, 2H), 4.68 (br s, 2H), 3.98 (s, 3H), 3.79 (s, 3H), 2.58-2.35 (m,2H), 0.97-0.86 (m, 3H) ppm; (M+1)=538.

Example 3-52: Synthesis of3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridineExample 3-52-1: Preparation of6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridine

To a stirred solution of5-iodo-N²-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)pyridine-2,3-diamine[prepared from 5-(chloromethyl)-2-(trifluoromethyl)pyridine using theprocedures described in Example 3-45-1 through Example 3-45-5] (0.710 g,1.30 mmol) in ethanol (30 mL) was added triethyl orthoformate (1.0 mL,5.89 mmol). The yellow solution was treated with p-toluenesulfonic acidmonohydrate (0.025 g, 0.13 mmol) and heated to reflux. After 30 min, themixture was allowed to cool to room temperature and was concentrated.The residue was partitioned between ethyl acetate (50 mL) and saturatedpotassium carbonate solution (50 mL). The phases were separated, and theorganic phase was dried over magnesium sulfate, filtered, andconcentrated to provide 0.739 g (>100%) of6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridineas an orange solid.

Example 3-52-2: Preparation of3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine

This compound was prepared from6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridineusing the procedure described in Example 3-49-5: ¹H NMR (400 MHz, CDCl₃)δ 8.78 (s, 1H), 8.55 (d, J=1.9 Hz, 1H), 8.15-7.93 (m, 3H), 7.79 (s, 1H),7.74-7.62 (m, 2H), 6.97-6.83 (m, 3H), 5.99 (q, J=7.1 Hz, 1H), 5.20 (s,2H), 3.98 (s, 3H), 3.83 (s, 3H), 2.00 (d, J=7.1 Hz, 3H) ppm; (M+1)=509.

Example 3-53: Synthesis of3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amineExample 3-53-1: Preparation of Ethyl(6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate

To a stirred solution of5-iodo-N²-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)pyridine-2,3-diamine[prepared from 5-(chloromethyl)-2-(trifluoromethyl)pyridine using theprocedures described in Example 3-45-1 through Example 3-45-5] (1.66 g,3.05 mmol) and triethylamine (0.64 mL, 4.57 mmol) in tetrahydrofuran (30mL) was added ethoxycarbonyl isothiocyanate (0.44 mL, 3.66 mmol). After30 min, the mixture was diluted with brine (100 mL) and extracted withethyl acetate (3×50 mL). The combined organic phases were dried overmagnesium sulfate, filtered, and concentrated to provide 2.18 g as abrown foamy solid. The crude material was dissolved in tetrahydrofuran(30 mL) and triethylamine (1.05 mL, 7.53 mmol). The light yellowsolution was treated with benzenesulfonyl chloride (0.97 mL, 7.51 mmol)and allowed to stir at room temperature. After 17 h, the mixture wasdiluted with water (100 mL) and allowed to stir at room temperature.After 15 min, the reaction mixture was extracted with dichloromethane(3×50 mL). The combined organic phases were washed with saturatedpotassium carbonate solution (50 mL), dried over magnesium sulfate,filtered, and concentrated to provide 2.77 g of a brown oil.Chromatographic purification (CombiFlash, 40 g SiO₂ gold column, 20-40%ethyl acetate/heptane elute) afforded 1.53 g (79%) of ethyl(6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamateas a tan solid.

Example 3-53-2: Preparation of6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-amine

To a stirred solution of ethyl(6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate(1.53 g, 2.39 mmol), in ethanol (10 mL)/water (4 mL) was added potassiumphosphate tribasic (2.07 g, 9.54 mmol). The mixture was irradiated in amicrowave reactor at 150° C. After 1 h, the mixture was subjected to anadditional round of microwave heating (160° C., 30 min). After a totalof 90 min, the mixture was diluted with water (100 mL) and extractedwith dichloromethane (2×50 mL). The combined organic phases were driedover magnesium sulfate, filtered, and concentrated to provide 1.31 g(97%) of6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-amineas an orange foamy solid.

Example 3-53-3: Preparation of3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

This compound was prepared from6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-amineusing the procedure described in Example 3-49-5: ¹H NMR (400 MHz, CDCl₃)δ 8.84-8.76 (m, 1H), 8.25 (d, J=1.9 Hz, 1H), 8.04-7.95 (m, 1H), 7.77 (d,J=0.8 Hz, 1H), 7.74-7.66 (m, 2H), 7.63 (d, J=0.8 Hz, 1H), 6.99-6.94 (m,1H), 6.94-6.86 (m, 2H), 6.12 (q, J=7.1 Hz, 1H), 5.23 (s, 2H), 4.37 (s,2H), 3.98 (s, 3H), 3.79 (s, 3H), 1.89 (d, J=7.1 Hz, 3H) ppm; (M+1)=524.

Example 3-54: Synthesis of2-(4-(2-amino-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)ethan-1-ol

This compound was prepared from6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-amineusing the procedure described in Example 3-49-5 by employing theappropriate boronate ester coupling partner: ¹H NMR (400 MHz, CDCl₃) δ8.84-8.76 (m, 1H), 8.23 (d, J=1.9 Hz, 1H), 8.03-7.95 (m, 1H), 7.80 (d,J=0.8 Hz, 1H), 7.73-7.70 (m, 2H), 7.66 (d, J=1.9 Hz, 1H), 7.01-6.85 (m,3H), 6.11 (q, J=7.1 Hz, 1H), 5.23 (s, 2H), 4.47 (s, 2H), 4.35-4.26 (m,2H), 4.10-4.03 (m, 2H), 3.79 (s, 3H), 1.88 (d, J=7.1 Hz, 3H), 1.70 (brs, 1H) ppm; (M+1)=554.

Example 3-55: Synthesis of4-(2-amino-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-6-yl)but-3-yn-1-ol

This compound was prepared from6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-amineusing the procedure described in Example 3-48-2: ¹H NMR (400 MHz, CDCl₃)δ 8.80 (d, J=2.0 Hz, 1H), 8.18 (d, J=1.7 Hz, 1H), 8.04-7.95 (m, 1H),7.72 (dd, J=8.1, 0.8 Hz, 1H), 7.64 (d, J=1.7 Hz, 1H), 6.98-6.88 (m, 2H),6.84 (d, J=2.0 Hz, 1H), 6.10 (q, J=7.1 Hz, 1H), 5.22 (s, 2H), 4.44 (brs, 2H), 3.85 (t, J=6.2 Hz, 2H), 3.79 (s, 3H), 2.74 (t, J=6.2 Hz, 2H),2.01 (br s, 1H), 1.86 (d, J=7.1 Hz, 3H) ppm; (M+1)=512.

Example 3-56: Synthesis of4-(3-(4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-6-yl)but-3-yn-1-olExample 3-56-1: Preparation of tert-butyl(4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzyl)carbamate

To a stirred solution of tert-butyl 4-hydroxy-3-methoxybenzylcarbamate(4.70 g, 18.56 mmol) and potassium carbonate (7.64 g, 55.28 mmol) inacetonitrile (50 mL) was added5-(chloromethyl)-2-(difluoromethyl)pyridine hydrochloride (4.58 g, 21.40mmol). The mixture was heated to reflux. After 3 h, the off-whitesuspension was allowed to cool to room temperature and was diluted withwater (200 mL). The mixture was extracted with dichloromethane (3×75mL). The combined organic phases were dried over magnesium sulfate,filtered, and concentrated to provide 7.74 g (>100%) of tert-butyl4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzylcarbamate asa waxy yellow solid.

Example 3-56-2: Preparation of(4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxyphenyl)methanamine

To a stirred solution of tert-butyl4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzylcarbamate(7.32 g, 18.56 mmol) in dichloromethane (30 ml) was addedtrifluoroacetic acid (15 mL, 194.70 mmol). After 2 h, the reactionmixture was concentrated, and the residue was dissolved in water (75mL). The acidic solution was extracted with diethyl ether (50 mL). Theaqueous phase was retained and made basic with concentrated ammoniumhydroxide solution (50 mL). The basic aqueous phase was extracted withdichloromethane (2×100 mL). The combined organic phases were dried overmagnesium sulfate, filtered, and concentrated to provide 4.54 g (83%) of(4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxyphenyl)methanamineas a yellow solid.

Example 3-56-3: Preparation of3-(4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5-b]pyridine

To a stirred solution ofN²-(4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzyl)-5-iodopyridine-2,3-diamine[prepared from(4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxyphenyl)methanamineusing the procedures described in Example 3-45-4 and Example 3-45-5](3.10 g, 6.05 mmol) in ethanol (50 mL) was added triethyl orthoformate(3.0 mL, 18.02 mmol). The mixture was treated with p-toluenesulfonicacid monohydrate (50 mg, 262.86 μmol) and was heated to reflux. After 45min, the mixture was allowed to cool to room temperature, resulting inthe formation of a precipitate. The mixture was concentrated, and theresidue dissolved in chloroform (150 mL). The solution was washed withsaturated potassium carbonate solution, dried over magnesium sulfate,filtered, and concentrated to provide 3.15 g (99%) of3-(4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5-b]pyridineas a brown solid.

Example 3-56-4: Preparation of4-(3-(4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-6-yl)but-3-yn-1-ol

This compound was prepared from3-(4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5-b]pyridineusing the procedure described in Example 3-48-2: ¹H NMR (400 MHz, CDCl₃)δ 8.71-8.69 (m, 1H), 8.48 (d, J=1.7 Hz, 1H), 8.10 (d, J=1.7 Hz, 1H),8.02 (s, 1H), 7.92 (dd, J=8.1, 2.1 Hz, 1H), 7.65 (d, J=8.1 Hz, 1H), 6.92(d, J=1.8 Hz, 1H), 6.87-6.80 (m, 2H), 6.64 (t, J=55.4 Hz, 1H), 5.38 (s,2H), 5.17 (s, 2H), 3.87 (t, J=6.3 Hz, 2H), 3.82 (s, 3H), 2.75 (t, J=6.3Hz, 2H), 2.11 (br s, 1H) ppm; (M+1)=465.

Example 3-57: Synthesis of3-(3-methoxy-4-(1-(6-methoxypyridin-3-yl)ethoxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridineFormate Example 3-57-1: Preparation of4-(((5-iodo-3-nitropyridin-2-yl)amino)methyl)-2-methoxyphenol

To a stirred suspension of 4-hydroxy-3-methoxybenzylamine hydrochloride(1.32 g, 6.82 mmol) and 2-chloro-5-iodo-3-nitropyridine (2.00 g, 6.82mmol) in acetonitrile (20 mL) was added N, N-disopropylethylamine (5.96ml, 34.10 mmol) The suspension was stirred and heated to 100° C. After 1h, the mixture was allowed to cool to room temperature, and 2N aqueouspotassium hydroxide solution (0.68 mL) was added. The mixture wasconcentrated to provide4-(((5-iodo-3-nitropyridin-2-yl)amino)methyl)-2-methoxyphenol as animpure solid.

Example 3-57-2: Preparation of4-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-methoxyphenol

This compound was prepared in two steps from4-(((5-iodo-3-nitropyridin-2-yl)amino)methyl)-2-methoxyphenol using theprocedures described in Example 3-49-2 and Example 3-52-2.

Example 3-57-3: Preparation of6-iodo-3-(3-methoxy-4-(1-(6-methoxypyridin-3-yl)ethoxy)benzyl)-3H-imidazo[4,5-b]pyridine

To a stirred mixture of4-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-methoxyphenol (1.32g, 3.46 mmol) and potassium carbonate (1.30 g, 9.41 mmol) inacetonitrile (25 mL) was added 5-(1-chloroethyl)-2-methoxypyridine (0.72g, 4.20 mmol). The mixture was heated at 100° C. After 6.5 h, anadditional quantity 5-(1-chloroethyl)-2-methoxypyridine (0.300 g, 1.75mmol) was added, and heating was continued. After 22 h, the mixture wasallowed to cool to room temperature and was partitioned between waterand 1:5 ethyl acetate/diethyl ether. The phases were separated, and theaqueous phase was extracted with diethyl ether. The combined organicphases were washed with water, dried over magnesium sulfate, filtered,and concentrated. Chromatographic purification (40 g SiO₂ column, 0-10%0.01 M ammonia in methanol/dichlormethane elute) afforded 0.88 g (49%)of6-iodo-3-(3-methoxy-4-(1-(6-methoxypyridin-3-yl)ethoxy)benzyl)-3H-imidazo[4,5-b]pyridineas an impure solid.

Example 3-57-4: Preparation of3-(3-methoxy-4-(1-(6-methoxypyridin-3-yl)ethoxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridineFormate

To a stirred suspension of6-iodo-3-(3-methoxy-4-(1-(6-methoxypyridin-3-yl)ethoxy)benzyl)-3H-imidazo[4,5-b]pyridine(0.200 g, 0.39 mmol), potassium phosphate tribasic (0.164 g, 0.77 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.100 g, 0.48 mmol) and tricyclohexylphosphine (0.008 g, 0.028 mmol) in1,4-dioxane (3 mL)/water (1.5 mL) was addedtris(dibenzylideneacetone)dipalladium(O) (0.012 g, 0.013 mmol). Themixture was degassed by bubbling nitrogen through the mixture for 2 min,and then the mixture was irradiated in a microwave reactor at 120° C.After 30 min, the mixture was allowed to cool to room temperature andwas filtered through Celite. The filtrate was subjected to directpurification (50 g C₁₈ column, water/acetonitrile/0.1% formic acidelute) to provide an impure material. A second purification under thesame conditions afforded 0.051 g (26%) of the product as a white solid:¹H NMR (400 MHz, CD₃D) δ 8.62 (d, J=1.9 Hz, 1H), 8.37 (s, 1H), 8.20-8.13(m, 1H), 8.05 (dd, J=7.6, 1.6 Hz, 2H), 7.90 (d, J=0.8 Hz, 1H), 7.71 (dd,J=8.6, 2.5 Hz, 1H), 7.05 (d, J=1.9 Hz, 1H), 6.83-6.69 (m, 3H), 5.42 (s,2H), 5.37 (q, J=6.4 Hz, 1H), 3.95 (s, 3H), 3.84 (s, 3H), 3.80 (s, 3H),1.58 (d, J=6.4 Hz, 3H) ppm; (M+1)=471.

Example 3-58: Synthesis of Additional Compounds from6-iodo-3-(3-methoxy-4-(1-(6-methoxypyridin-3-yl)ethoxy)benzyl)-3H-imidazo[4,5-b]pyridine

The following compounds were prepared from6-iodo-3-(3-methoxy-4-(1-(6-methoxypyridin-3-yl)ethoxy)benzyl)-3H-imidazo[4,5-b]pyridineusing the procedure described in Example 3-57-4 by employing theappropriate boronic acid/boronate ester coupling partner.

Example 3-58-1:3-(3-methoxy-4-(1-(6-methoxypyridin-3-yl)ethoxy)benzyl)-6-(1-methyl-1H-pyrazol-5-yl)-3H-imidazo[4,5-b]pyridineFormate (RA09683914A)

¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J=1.9 Hz, 1H), 8.17-8.03 (m, 3H),7.64 (dd, J=8.6, 2.5 Hz, 1H), 7.57 (d, J=1.9 Hz, 1H), 6.90 (d, J=1.5 Hz,1H), 6.78-6.65 (m, 3H), 6.39 (d, J=1.9 Hz, 1H), 5.39 (s, 2H), 5.29 (q,J=6.4 Hz, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.83 (s, 3H), 3.49 (s, 1H),1.66 (d, J=6.4 Hz, 3H) ppm; (M+1)=471.

Example 3-58-2:3-(3-methoxy-4-(1-(6-methoxypyridin-3-yl)ethoxy)benzyl)-6-(6-methoxypyridin-3-yl)-3H-imidazo[4,5-b]pyridineFormate (RA09683951A)

¹H NMR (400 MHz, CDCl₃) δ 8.59 (d, J=2.0 Hz, 1H), 8.42 (dd, J=2.6, 0.8Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 8.10 (d, J=2.4 Hz, 1H), 8.03 (s, 1H),7.82 (dd, J=8.6, 2.6 Hz, 1H), 7.63 (dd, J=8.6, 2.5 Hz, 1H), 6.89 (d,J=0.9 Hz, 2H), 6.75-6.66 (m, 3H), 5.38 (s, 2H), 5.29 (q, J=6.4 Hz, 1H),4.00 (s, 3H), 3.90 (s, 3H), 3.82 (s, 3H), 1.66 (d, J=6.5 Hz, 3H) ppm;(M+1)=498.

Example 3-58-3:6-(2-fluoropyridin-4-yl)-3-(3-methoxy-4-(1-(6-methoxypyridin-3-yl)ethoxy)benzyl)-3H-imidazo[4,5-b]pyridineFormate (RA09683967A)

¹H NMR (400 MHz, CDCl₃) δ 8.70 (d, J=2.0 Hz, 1H), 8.35-8.29 (m, 2H),8.10 (d, J=2.8 Hz, 2H), 7.64 (dd, J=8.6, 2.5 Hz, 1H), 7.46 (dt, J=5.3,1.7 Hz, 1H), 7.19 (t, J=1.6 Hz, 1H), 6.89 (d, J=1.5 Hz, 1H), 6.75-6.72(m, 2H), 6.71 (dd, J=8.6, 0.7 Hz, 1H), 5.39 (s, 2H), 5.29 (q, J=6.4 Hz,1H), 3.90 (s, 3H), 3.83 (s, 3H), 1.66 (d, J=6.4 Hz, 3H) ppm; (M+1)=486.

The invention claimed is:
 1. A method of inhibiting tropomyosin-relatedkinase A in a patient, comprising administering to the patient apharmaceutical composition comprising a compound of Formula (I) in orderto inhibit tropomyosin-related kinase A in the patient, wherein FormulaI is represented by:

or a pharmaceutically acceptable salt thereof; wherein: n is 1, 2, 3, 4or 5; m is 0, 1, 2, 3 or 4; Q¹ is (C₂-C₉)heteroaryl optionallysubstituted by one to four groups selected from (C₁-C₁₀)alkyl,(C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl,(C₆-C₁₄)aryl, (C₂-C₉)heteroaryl, (C₁-C₁₀)alkylamine,(C₁-C₁₀)alkyl-C(O)O—, COOH—(C₁-C₁₀)alkyl, COOH—(C₃-C₁₀)cycloalkyl,(C₁-C₁₀)alkyl-O—, —OH, —NH₂, R⁷R⁸N—, R⁷R⁸N(O)C—, R⁷(O)CR⁸N—, F₃C—, NC—,(C₃-C₁₀)alkyl-S—, (C₃-C₁₀)cycloalkyl-S—, (C₆-C₁₄)aryl-S—,(C₂-C₉)heteroalkyl-S—, (C₂-C₉)heterocycloalkyl-S—, (C₂-C₉)heteroaryl-S—,(C₃-C₁₀)alkyl(O)S—, (C₃-C₁₀)cycloalkyl(O)S—, (C₆-C₁₄)aryl(O)S—,(C₂-C₉)heteroalkyl(O)S—, (C₂-C₉)heterocycloalkyl(O)S—,(C₂-C₉)heteroaryl(O)S—, (C₃-C₁₀)alkyl-O₂S—, (C₃-C₁₀)cycloalkyl-O₂S—,(C₆-C₁₄)aryl-O₂S—, (C₂-C₉)heteroalkyl-O₂S—,(C₂-C₉)heterocycloalkyl-O₂S—, (C₂-C₉)heteroaryl-O₂S—, or R⁷R⁸NO₂S—,wherein R⁷ and R⁸ is each independently H, (C₁-C₁₀)alkyl,(C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl,(C₆-C₁₄)aryl, or (C₂-C₉)heteroaryl; Q² is (C₆-C₁₄)aryl,(C₂-C₉)heteroaryl, (C₃-C₁₀)cycloalkyl, or (C₂-C₉)heterocycloalkyl,wherein the (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl, (C₃-C₁₀)cycloalkyl, or(C₂-C₉)heterocycloalkyl is optionally substituted by one to four groupsselected from (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,(C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,(C₁-C₁₀)alkylamine, (C₁-C₁₀)alkyl-C(O)O—, COOH—(C₁-C₁₀)alkyl,COOH—(C₃-C₁₀)cycloalkyl, (C₁-C₁₀)alkyl-O—, —OH, —NH₂, R⁷R⁸N—,R⁷R⁸N(O)C—, R⁷(O)CR⁸N—, F₃C—, NC—, (C₃-C₁₀)alkyl-S—,(C₃-C₁₀)cycloalkyl-S—, (C₆-C₁₄)aryl-S—, (C₂-C₉)heteroalkyl-S—,(C₂-C₉)heterocycloalkyl-S—, (C₂-C₉)heteroaryl-S—, (C₃-C₁₀)alkyl(O)S—,(C₃-C₁₀)cycloalkyl(O)S—, (C₆-C₁₄)aryl(O)S—, (C₂-C₉)heteroalkyl(O)S—,(C₂-C₉)heterocycloalkyl(O)S—, (C₂-C₉)heteroaryl(O)S—,(C₃-C₁₀)alkyl-O₂S—, (C₃-C₁₀)cycloalkyl-O₂S—, (C₆-C₁₄)aryl-O₂S—,(C₂-C₉)heteroalkyl-O₂S—, (C₂-C₉)heterocycloalkyl-O₂S—,(C₂-C₉)heteroaryl-O₂S—, or R⁷R⁸NO₂S—, wherein R⁷ and R⁸ is eachindependently H, (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl, (C₃-C₁₀)cycloalkyl,(C₂-C₉)heterocycloalkyl, (C₆-C₁₄)aryl, or (C₂-C₉)heteroaryl; X is CH, N,or CR⁹, wherein R⁹ is (C₁-C₁₀)alkyl; R¹ is H, (C₁-C₁₀)alkylamine, orNH₂; R² is (C₁-C₁₀)alkylamine or (C₁-C₁₀)alkyl-O—; R³ and R⁴ are eachindependently H or (C₁-C₁₀)alkyl; and R⁵ and R⁶ are each independently Hor (C₁-C₁₀)alkyl.
 2. The method of claim 1, wherein Q¹ is(C₂-C₉)heteroaryl substituted by (C₁-C₁₀)alkyl.
 3. The method of claim1, wherein Q² is (C₆-C₁₄)aryl substituted by (C₁-C₁₀)alkyl-O—.
 4. Themethod of claim 2, wherein Q² is (C₆-C₁₄)aryl substituted by(C₁-C₁₀)alkyl-O—.
 5. The method of claim 1, wherein X is N.
 6. Themethod of claim 4, wherein X is N.
 7. The method of claim 1, wherein R¹is NH₂.
 8. The method of claim 6, wherein R¹ is NH₂.
 9. The method ofclaim 1, wherein R² is (C₁-C₁₀)alkyl-O—.
 10. The method of claim 8,wherein R² is (C₁-C₁₀)alkyl-O—.
 11. The method of claim 1, wherein thecompound is represented by Formula II:

or a pharmaceutically acceptable salt thereof, wherein: n is 1, 2, or 3;m is 0, 1, 2, or 3; Q¹ is (C₂-C₉)heteroaryl optionally substituted byone to four groups selected from (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₁-C₁₀)alkylamine,(C₁-C₁₀)alkyl-C(O)O—, (C₁-C₁₀)alkyl-O—, —OH, or —NH₂; Q² is(C₆-C₁₄)aryl, (C₂-C₉)heteroaryl, (C₃-C₁₀)cycloalkyl, or(C₂-C₉)heterocycloalkyl, wherein the (C₆-C₁₄)aryl, (C₂-C₉)heteroaryl,(C₃-C₁₀)cycloalkyl, or (C₂-C₉)heterocycloalkyl is optionally substitutedby one to four groups selected from (C₁-C₁₀)alkyl, (C₂-C₉)heteroalkyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, (C₁-C₁₀)alkylamine,(C₁-C₁₀)alkyl-C(O)O—, (C₁-C₁₀)alkyl-O—, —OH, or —NH₂; X is CH, N, orCR⁹, wherein R⁹ is (C₁-C₁₀)alkyl; R¹ is (C₁-C₁₀)alkylamine or NH₂; andR² is (C₁-C₁₀)alkylamine or (C₁-C₁₀)alkyl-O—.
 12. The method of claim11, wherein Q¹ is (C₂-C₉)heteroaryl substituted by (C₁-C₁₀)alkyl. 13.The method of claim 11, wherein Q² is (C₆-C₁₄)aryl substituted by(C₁-C₁₀)alkyl-O—.
 14. The method of claim 12, wherein Q² is (C₆-C₁₄)arylsubstituted by (C₁-C₁₀)alkyl-O—.
 15. The method of claim 11, wherein Xis N.
 16. The method of claim 14, wherein X is N.
 17. The method ofclaim 11, wherein R¹ is NH₂.
 18. The method of claim 16, wherein R¹ isNH₂.
 19. The method of claim 11, wherein R² is (C₁-C₁₀)alkyl-O—.
 20. Themethod of claim 18, wherein R² is (C₁-C₁₀)alkyl-O—.
 21. The method ofclaim 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.